Chemical detection device having multiple flow channels

ABSTRACT

The described embodiments may provide a chemical detection circuit that may comprise a plurality of first output circuits at a first side and a plurality of second output circuits at a second side of the chemical detection circuit. The chemical detection circuit may further comprise a plurality of tiles of pixels each placed between respective pairs of first and second output circuits. Each tile may include four quadrants of pixels. Each quadrant may have columns with designated first columns interleaved with second columns. Each first column may be coupled to a respective first output circuit in first and second quadrants, and to a respective second output circuit in third and fourth quadrants. Each second column may be coupled to a respective second output circuit in first and second quadrants, and to a respective first output circuit in third and fourth quadrants.

RELATED APPLICATIONS

This application is a continuation application of pending U.S.application Ser. No. 15/292,795 filed Oct. 13, 2016, which is adivisional of U.S. application Ser. No. 14/597,507 filed Jan. 15, 2015(now abandoned), which is a continuation of U.S. application Ser. No.13/861,237 filed Apr. 11, 2013 (now U.S. Pat. No. 8,983,783), which is acontinuation of U.S. patent application Ser. No. 13/174,514 filed Jun.30, 2011 (now U.S. Pat. No. 8,731,847), which claims the benefit of U.S.Provisional Application No. 61/360,493 filed Jun. 30, 2010, U.S.Provisional Application No. 61/360,495 filed Jul. 1, 2010, U.S.Provisional Application No. 61/361,403 filed Jul. 3, 2010, and U.S.Provisional Application No. 61/365,327 filed Jul. 17, 2010. All of theaforementioned applications are incorporated herein by reference, eachin their entirety.

BACKGROUND

Electronic devices and components have found numerous applications inchemistry and biology (more generally, “life sciences”), especially fordetection and measurement of various chemical and biological reactionsand identification, detection and measurement of various compounds. Onesuch electronic device is referred to as an ion-sensitive field effecttransistor, often denoted in the relevant literature as an “ISFET” (orpHFET). ISFETs conventionally have been explored, primarily in theacademic and research community, to facilitate measurement of thehydrogen ion concentration of a solution (commonly denoted as “pH”).

More specifically, an ISFET is an impedance transformation device thatoperates in a manner similar to that of a Metal Oxide SemiconductorField Effect Transistor (MOSFET), and is particularly configured toselectively measure ion activity in a solution (e.g., hydrogen ions inthe solution are “analytes”). A detailed theory of operation of an ISFETis given in “Thirty years of ISFETOLOGY: what happened in the past 30years and what may happen in the next 30 years,” P. Bergveld, Sens.Actuators, 88 (2003), pp. 1-20 (“Bergveld”), which publication is herebyincorporated herein by reference in its entirety.

Details of fabricating an ISFET using a conventional Complementary MetalOxide Semiconductor (CMOS) process may be found in Rothberg, et al.,U.S. Patent Publication No. 2010/0301398, Rothberg, et al., U.S. PatentPublication No. 2010/0282617, and Rothberg et al., U.S. PatentPublication 2009/0026082; these patent publications are collectivelyreferred to as “Rothberg,” and are all incorporated herein by referencein their entireties. In addition to CMOS, bipolar and CMOS (biCMOS)processing may be used, such as a process that would include a p-channelMOS FET array with bipolar structures on the periphery. Alternatively,other technologies may be employed where a sensing element can be madewith a three-terminal devices in which a sensed ion leads to thedevelopment of a signal that controls one of the three terminals; suchtechnologies may also include, for example, Gallium Arenides (GaAs) andcarbon nanotube technologies.

Taking a CMOS example, a P-type ISFET fabrication is based on a p-typesilicon substrate, in which an n-type well forms a “body” of thetransistor. Highly-doped p-type (p+) source (S) and drain (D) regions,are formed within the n-type well. A highly-doped n-type (n+) region Bmay also be formed within the n-type well to provide a conductive body(or “bulk”) connection to the n-type well. An oxide layer may bedisposed above the source, drain and body connection regions, throughwhich openings are made to provide electrical connections (viaelectrical conductors) to these regions. A polysilicon gate may beformed above the oxide layer at a location above a region of the n-typewell, between the source and the drain. Because it is disposed betweenthe polysilicon gate and the transistor body (i.e., the n-type well),the oxide layer often is referred to as the “gate oxide.”

Like a MOSFET, the operation of an ISFET is based on the modulation ofcharge concentration (and thus channel conductance) caused by aMetal-Oxide-Semiconductor (MOS) capacitance. This capacitance isconstituted by a polysilicon gate, a gate oxide and a region of the well(e.g., n-type well) between the source and the drain. When a negativevoltage is applied across the gate and source regions, a channel iscreated at the interface of the region and the gate oxide by depletingthis area of electrons. For an n-well, the channel would be a p-channel.In the case of an n-well, the p-channel would extend between the sourceand the drain, and electric current is conducted through the p-channelwhen the gate-source potential is negative enough to attract holes fromthe source into the channel. The gate-source potential at which thechannel begins to conduct current is referred to as the transistor'sthreshold voltage VTH (the transistor conducts when VGS has an absolutevalue greater than the threshold voltage VTH). The source is so namedbecause it is the source of the charge carriers (holes for a p-channel)that flow through the channel; similarly, the drain is where the chargecarriers leave the channel.

As described in Rothberg, an ISFET may be fabricated with a floatinggate structure, formed by coupling a polysilicon gate to multiple metallayers disposed within one or more additional oxide layers disposedabove the gate oxide. The floating gate structure is so named because itis electrically isolated from other conductors associated with theISFET; namely, it is sandwiched between the gate oxide and a passivationlayer that is disposed over a metal layer (e.g., top metal layer) of thefloating gage.

As further described in Rothberg, the ISFET passivation layerconstitutes an ion-sensitive membrane that gives rise to theion-sensitivity of the device. The presence of analytes such as ions inan analyte solution (i.e., a solution containing analytes (includingions) of interest or being tested for the presence of analytes ofinterest), in contact with the passivation layer, particularly in asensitive area that may lie above the floating gate structure, altersthe electrical characteristics of the ISFET so as to modulate a currentflowing through the channel between the source and the drain of theISFET. The passivation layer may comprise any one of a variety ofdifferent materials to facilitate sensitivity to particular ions; forexample, passivation layers comprising silicon nitride or siliconoxynitride, as well as metal oxides such as silicon, aluminum ortantalum oxides, generally provide sensitivity to hydrogen ionconcentration (pH) in an analyte solution, whereas passivation layerscomprising polyvinyl chloride containing valinomycin provide sensitivityto potassium ion concentration in an analyte solution. Materialssuitable for passivation layers and sensitive to other ions such assodium, silver, iron, bromine, iodine, calcium, and nitrate, forexample, are known, and passivation layers may comprise variousmaterials (e.g., metal oxides, metal nitrides, and metal oxynitrides).Regarding the chemical reactions at the analyte solution/passivationlayer interface, the surface of a given material employed for thepassivation layer of the ISFET may include chemical groups that maydonate protons to or accept protons from the analyte solution, leavingat any given time negatively charged, positively charged, and neutralsites on the surface of the passivation layer at the interface with theanalyte solution.

With respect to ion sensitivity, an electric potential difference,commonly referred to as a “surface potential,” arises at thesolid/liquid interface of the passivation layer and the analyte solutionas a function of the ion concentration in the sensitive area due to achemical reaction (e.g., usually involving the dissociation of oxidesurface groups by the ions in the analyte solution in proximity to thesensitive area). This surface potential in turn affects the thresholdvoltage of the ISFET; thus, it is the threshold voltage of the ISFETthat varies with changes in ion concentration in the analyte solution inproximity to the sensitive area. As described in Rothberg, since thethreshold voltage VTH of the ISFET is sensitive to ion concentration,the source voltage VS provides a signal that is directly related to theion concentration in the analyte solution in proximity to the sensitivearea of the ISFET.

Arrays of chemically-sensitive FETs (“chemFETs”), or more specificallyISFETs, may be used for monitoring reactions—including, for example,nucleic acid (e.g., DNA) sequencing reactions, based on monitoringanalytes present, generated or used during a reaction. More generally,arrays including large arrays of chemFETs may be employed to detect andmeasure static and/or dynamic amounts or concentrations of a variety ofanalytes (e.g., hydrogen ions, other ions, non-ionic molecules orcompounds, etc.) in a variety of chemical and/or biological processes(e.g., biological or chemical reactions, cell or tissue cultures ormonitoring, neural activity, nucleic acid sequencing, etc.) in whichvaluable information may be obtained based on such analyte measurements.Such chemFET arrays may be employed in methods that detect analytesand/or methods that monitor biological or chemical processes via changesin charge at the chemFET surface. Such use of chemFET (or ISFET) arraysinvolves detection of analytes in solution and/or detection of change incharge bound to the chemFET surface (e.g. ISFET passivation layer).

Research concerning ISFET array fabrication is reported in thepublications “A large transistor-based sensor array chip for directextracellular imaging,” M. J. Milgrew, M. O. Riehle, and D. R. S.Cumming, Sensors and Actuators, B: Chemical, 111-112, (2005), pp.347-353, and “The development of scalable sensor arrays using standardCMOS technology,” M. J. Milgrew, P. A. Hammond, and D. R. S. Cumming,Sensors and Actuators, B: Chemical, 103, (2004), pp. 37-42, whichpublications are incorporated herein by reference and collectivelyreferred to hereafter as “Milgrew et al.” Descriptions of fabricatingand using ChemFET or ISFET arrays for chemical detection, includingdetection of ions in connection with DNA sequencing, are contained inRothberg. More specifically, Rothberg describes using a chemFET array(in particular ISFETs) for sequencing a nucleic acid involvingincorporation of known nucleotides into a plurality of identical nucleicacids in a reaction chamber in contact with or capacitively coupled tothe chemFET, wherein the nucleic acids are bound to a single bead in thereaction chamber, and detecting a signal at the chemFET, whereindetection of the signal indicates release of one or more hydrogen ionsresulting from incorporation of the known nucleotide triphosphate intothe synthesized nucleic acid.

However, with the scaling of ISFET sensor array designs, more and moreISFET sensors are packed on a chip. Thus, there is a need in the art toprovide a readout scheme to output measured data from a chip at a highspeed.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 illustrates a 1T ion sensitive pixel according to an embodimentof the present invention.

FIG. 2 illustrates the cross section of a 1T pixel according to anembodiment of the present invention.

FIG. 3 shows the schematic of an array of pixels with column readoutswitches according to an embodiment of the present invention.

FIG. 4 shows the source follower configuration of the 1T pixel accordingto an embodiment of the present invention.

FIG. 5A shows a 1T common source ion sensitive pixel according to anembodiment of the present invention.

FIG. 5B shows the pixel in a common source readout configurationaccording to an embodiment of the present invention.

FIG. 5C shows a common source equivalent circuit according to anembodiment of the present invention.

FIG. 6 shows a schematic of an array of pixels with column readoutswitches according to an embodiment of the present invention.

FIG. 7A shows a cross section of a 1T common source pixel according toan embodiment of the present invention.

FIG. 7B shows a cross section of a 1T common source pixel according toan embodiment of the present invention.

FIG. 8 shows a common source pixel with a cascoded row selection deviceaccording to an embodiment of the present invention.

FIG. 9 shows a one-transistor pixel array with cascaded column circuitaccording to an embodiment of the present invention.

FIGS. 10A and 10B show a one-transistor pixel array according to anembodiment of the present invention.

FIG. 11 shows a two-transistor (2T) pixel according to an embodiment ofthe present invention.

FIG. 12A to 12H illustrate 2T pixel configurations according toembodiments of the present invention.

FIG. 13A to 13D illustrate common source 2T cell configurationsaccording to embodiments of the present invention.

FIG. 14A shows a 2T pixel array according to an embodiment of thepresent invention.

FIGS. 14B and 14C show a layout for a 2×2 2T pixel array according to anembodiment of the present invention.

FIG. 15 shows a capacitive charge pump according to an embodiment of thepresent invention.

FIG. 16 shows a charge pump according to an embodiment of the presentinvention.

FIG. 17 shows a charge pump according to an embodiment of the presentinvention.

FIG. 18 shows a charge pump according to an embodiment of the presentinvention.

FIG. 19 shows a basic IS accumulation pixel according to an embodimentof the present invention.

FIG. 20A to 20P show surface potential diagrams for basic chargeaccumulation according to an embodiment of the present invention.

FIGS. 21 and 22 show an IS accumulation pixel with 2 transistorsaccording to an embodiment of the present invention.

FIG. 23 shows surface potential diagrams for the pixel of FIG. 22according to an embodiment of the present invention.

FIG. 24 shows an IS accumulation pixel with 2 transistors and 4electrodes according to an embodiment of the present invention.

FIG. 25 shows the surface potential diagrams for the pixel of FIG. 24according to an embodiment of the present invention.

FIG. 26 shows an IS accumulation pixel with 1 transistor and 3electrodes according to an embodiment of the present invention.

FIG. 27 shows a three transistor (3T) active pixel sensor according toan embodiment of the present invention.

FIG. 28 shows an alternate embodiment of a 3T active pixel sensor.

FIG. 29 shows a 3T active pixel sensor with a sample and hold circuitaccording to an embodiment of the present invention.

FIG. 30 shows a 3T active pixel sensor with a correlated double samplingcircuit according to an embodiment of the present invention.

FIG. 31 shows a 2.5T active pixel sensor array according to anembodiment of the present invention.

FIG. 32 shows a 1.75T active pixel sensor array according to anembodiment of the present invention.

FIG. 33 illustrates a block diagram of a chemical detection circuitaccording to an embodiment of the present invention.

FIG. 34 illustrates a block diagram of another chemical detectioncircuit according to another embodiment of the present invention.

FIG. 35 illustrates a block diagram of yet another chemical detectioncircuit according to yet another embodiment of the present invention.

FIG. 36 illustrates a process for generating an output of a chemicaldetection circuit according to an embodiment of the present invention.

FIG. 37 illustrates a block diagram of a chemical detection circuitaccording to an embodiment of the present invention.

FIG. 38A illustrates a block diagram of components of a chemicaldetection circuit according to an embodiment of the present invention.

FIG. 38B illustrates shift directions in different quadrants of a tileaccording to an embodiment of the present invention.

FIG. 39 illustrates a block diagram of a channel of a chemical detectioncircuit according to an embodiment of the present invention.

FIG. 40 illustrates a swizzle configuration of signal lines of achemical detection circuit according to an embodiment of the presentinvention.

FIG. 41 illustrates a process for output data from a chemical detectioncircuit according to an embodiment of the present invention.

FIG. 42 illustrates a system architecture for chemical detectionaccording to an embodiment of the present invention.

FIG. 43 illustrates an analog reader board for a chemical detectioncircuit according to an embodiment of the present invention.

FIG. 44 illustrates a digital reader board for a chemical detectioncircuit according to an embodiment of the present invention.

FIG. 45 illustrates a block diagram of analog front end and noisecalculations for a chemical detection circuit according to an embodimentof the present invention.

FIG. 46 illustrates a block diagram of bandwidth utilization for achemical detection circuit according to an embodiment of the presentinvention.

FIG. 47 illustrates a block diagram for clock distribution according toan embodiment of the present invention.

FIG. 48 illustrates a block diagram for power distribution according toan embodiment of the present invention.

FIG. 49 illustrates a block diagram for digital-to-analog converts(DACs) of an analog reader board according to an embodiment of thepresent invention.

FIG. 50 illustrates a block diagram of field-programmable gate array(FPGA) configuration according to an embodiment of the presentinvention.

FIG. 51 illustrates a block diagram of FPGA power monitoring accordingto an embodiment of the present invention.

FIG. 52 illustrates a digital chemical detection circuit according to anembodiment of the present invention.

FIG. 53 illustrates a more detailed block diagram of the digitalchemical detection circuit of FIG. 52 according to an embodiment of thepresent invention.

FIG. 54 illustrates a serializer circuit according to an embodiment ofthe present invention.

FIG. 55 illustrates a more detailed block diagram of the serializer ofFIG. 54 according to an embodiment of the present invention.

FIG. 56 illustrates a block diagram of a digital chemical detectioncircuit according to an embodiment of the present invention.

FIG. 57 illustrates a block diagram of another digital chemicaldetection circuit according to an embodiment of the present invention.

FIG. 58 illustrates a block diagram of another digital chemicaldetection circuit according to an embodiment of the present invention.

DETAILED DESCRIPTION One-Transistor Pixel Array

A floating gate (FG) transistor may be used to detect ions in closeproximity to the gate electrode. The transistor may be configured withother transistors to form a pixel that can be placed into an array foraddressable readout. In the simplest form, the ancillary transistors areused solely to isolate and select the floating gate transistor forreadout in an array. The floating gate transistor may be achemically-sensitive transistor, and more specifically, achemically-sensitive field effect transistor (ChemFET). The ChemFET maybe designed with a metal-oxide-semiconductor field-effect transistor(MOSFET) containing self-aligned source and drain implants fabricatedusing standard complementary metal-oxide-semiconductor (CMOS)processing. The ChemFET may be an ion sensitive FET (ISFET), and may bea PMOS or an NMOS device.

A floating gate (FG) transistor may be used to detect ions in closeproximity to the gate electrode. The transistor may be configured withother transistors to form a pixel that can be placed into an array foraddressable readout. In the simplest form, the ancillary transistors areused solely to isolate and select the floating gate transistor forreadout in an array. The floating gate transistor may be achemically-sensitive transistor, and more specifically, achemically-sensitive field effect transistor (ChemFET). The ChemFET maybe designed with a metal-oxide-semiconductor field-effect transistor(MOSFET) containing self-aligned source and drain implants fabricatedusing standard complementary metal-oxide-semiconductor (CMOS)processing. The ChemFET may be an ion sensitive FET (ISFET), and may bea PMOS or an NMOS device.

To reduce the pixel size to the smallest dimensions and simplest form ofoperation, the ancillary transistors may be eliminated to form an ionsensitive field-effect transistor (ISFET) using one transistor. Thisone-transistor, or 1T, pixel can provide gain by converting the draincurrent to voltage in the column. Parasitic overlap capacitance betweenterminals of the transistor limits the gain. The capacitance ratios alsoallow consistent pixel-to-pixel gain matching and relatively constantcurrent operation which justifies the use of a row selection line whichcan sink the necessary current without causing unacceptable variation.Derivatives of this allow for increased programmable gain through acascoded transistor enabled during readout. Configurable pixels can becreated to allow both common source read out as well as source followerread out.

FIG. 1 illustrates a 1T ion sensitive pixel according to one embodimentof the present invention. As shown, the pixel 100 may have one and onlyone transistor 101, one and only one row line R and one and only onecolumn line C. The transistor 101 is shown as an n-channel MOSFET (NMOS)transistor in a p-type epitaxial substrate available using standard CMOSprocesses in this embodiment. It should be understood that NMOS is onlyused as an example in the present invention, and the transistor 101 maybe a PMOS as well. The selection of NMOS or PMOS as a preferred devicedepends on which device does not require a top-side bulk contact for agiven process. Typically NMOS is preferred when using a P+ wafer with P−epitaxy layer (called an epi-wafer) because the underlying P+ substratebiases the bulk on an array of pixels without the need to wire in a bulkcontact at each pixel location. Therefore, a global bulk contact is anattractive combination for use with a 1T pixel where a small pixel pitchis required. The floating gate G of the transistor 101 may containtrapped charge, which may be properly discharged such that the electrodeis at approximately the same potential as the substrate when all otherterminals are also biased to the substrate potential. The row line R maybe capacitively coupled to the drain D of the transistor 101, and thecolumn line may be coupled to the source S of the transistor 101. A gateto drain overlap capacitance Cgd may form between the gate G and thedrain D. The pixel 100 may be addressable from the row line R, whichsupplies the column current (i.e., drain-to-source current of thetransistor 101) and boosts the potential at the floating gate.

In a one-transistor pixel array, such as the one shown in FIG. 3, rowselection may be facilitated by boosting the FG nodes for a particularrow. In one embodiment, the readout of the pixel is a winner-take-allcircuit, which will be described below.

FIG. 2 illustrates the cross section of a 1T pixel according to oneembodiment of the present invention. The transistor in the 1T pixel maybe formed using an n-channel FET device by having a drain D and a sourceS formed using n-type implants within a p-type semiconductor. As shown,the transistor may have a floating gate G, the drain D and the source S.The source S may be coupled to the column line C and the drain D may becoupled to the row line R. Lightly doped drain (LDD) regions may createa gate to drain overlap capacitance Cgd and/or a gate to source overlapcapacitance Cgs.

In one embodiment, the 1T ion pixel 100 may work by boot-strapping therow selection line R to the floating gate G while at the same timeproviding a source of current for the column line bias. In the simplestform, this bootstrapping occurs without adding any extra capacitors. Thegate to drain overlap capacitance Cgd, as shown in FIGS. 1 and 2, maynaturally form the necessary capacitive coupling. To increase capacitivecoupling, if desired, the row selection metal line can form an extrametal capacitor to the floating metal electrode or more significantsource and drain extensions can be made with ion implantation.

FIG. 3 shows the schematic of an array of pixels with column readoutswitches according to one embodiment of the present invention. Forillustrative purposes, four 1T pixels 301, 302, 303 and 304 of an array300 are shown arranged into two rows and two columns, though the array300 could extend to an array of any size of 1T pixels. The 1T pixel maybe similar to the one shown in FIG. 1. The drains of pixels 301 and 302are coupled to a row line R0, and the sources of pixels 301 and 302 arecoupled to column lines C0 and C1 respectively. The drains of pixels 303and 304 are coupled to a row line R1, and the sources of pixels 303 and304 are coupled to column lines C0 and C1 respectively. The pixel arraycan be loaded with a current source but the simplest implementationmakes use of just a single switch that precharges the column line to alow potential such as the substrate potential. A column readout switch305 is coupled to the column line C0 and a column readout switch 306 iscoupled to the column line C1. The column readout switch 305 comprises aswitch Sa, a switch Sb, a current source Isource and a capacitor Cw. Theswitch Sa is used for precharging the column line and to initialize thecolumn line quickly between samples. The switch Sb is used to sample andhold the analog value that is read on the column line. In some cases,neither a sampling capacitor nor a switch Sb are required if the pixelis converted to digital through and analog to digital converter whilethe pixel is held under bias. The switch Sa is used to ground the columnline C0. After the column line switch Sb is open the sample is held inthe capacitor, the final value on the column line, as sampled by thecapacitor, will be determined almost entirely by the active row becausethe circuit operates according to “a winner take-all” mode (i.e., theresulting voltage represents the largest voltage of the ISFETs coupledto the readout circuit). The column readout circuit 306 functionssimilarly.

The operation of this pixel depends on the fact that the signal range ofany given pixel is small compared to the supply voltage or read range ofthe source follower. For example, the useful signal range may be only100 mV and the supply voltage may be 3.3V. When a row is selected, the Rline is driven to an active high voltage VH, while all other row linesare held at an active low voltage VL. The voltage VL is selected to beapproximately equal to the nominal voltage on the column line C duringthe readout of any given pixel. Because the signal range is small, thisvoltage is known to within 100 mV in this example. Therefore, the drainto source voltage of all inactive pixels is always held to small values.This point is only critical if the gate to source voltage of inactivepixels is near the threshold of the device. For the row driven to VH,the FG voltages for that row are significantly higher than the otherrows because of the bootstrapping that occurs when the row linetransitions to VH. After the column line switch Sb is open, the finalvalue on the column line will be determined almost entirely by theactive row because the circuit operates according to the winner take-allmode.

There are two sources of current from other rows that can distort thesignal value (one that adds current and one that takes away current) andthere must be enough bootstrapping available to successfully read pixelswithout significant interaction from the other rows that produce thesesources. The analysis to determine how much bootstrapping is needed isas follows. By the time the pixel is sampled, the device has entered thesubthreshold region of operation which has a transconductance slope, forexample, of approximately 100 mV/decade. This means that for every 100mV of change in gate voltage, the current changes by 10 times. In orderto effectively read a single pixel, a criteria is set so that 99% of thecurrent on the column line is attributable to the active row and only 1%is attributable to the inactive rows (distortion current). From here itcan be determined how much bootstrapping is necessary. With only 2 rowsin the pixel array, a 200 mV difference in the floating gate voltages isneeded according to the subthreshold slope. Since a signal range ofabout 100 mV is also needed to be accounted for, the total requirementis about 300 mV. If there are 10 rows, there may be 10 times morecontribution from inactive rows. Therefore an extra 100 mV is needed. Ifthe array is increased to 100 rows, another 100 mV is needed. If thearray is increased to 10̂n rows, 300+100*n mV is needed. As an example, a10000 (10̂4) row pixel array only requires a total of 700 mV (300+100*4)of bootstrapping. This amount of bootstrapping can be achieved from theoverlap capacitance of the gate and drain. If more capacitance isneeded, extra coupling can be facilitated in the mask layout. The aboveanalysis only applies to pixels contributing to the readout current.

Pixels can also take current away from the column line and sink itthrough the deactivated row lines. Since the deactivated row line is setto approximately the level of the column line, this current draw will beminimal but it must still be quantified and controlled. To accomplishthis, the final current on the column line should not be allowed todiminish beyond a certain level. This is ensured by loading the columnwith a small current sink such as 1 uA. For a W/L (width to length)ratio of 1, a transistor biased at its threshold will have a saturationcurrent of about 0.1 uA. This current decreases by a factor of 10 forevery 100 mV of reduction in gate to source voltage. If less than 1%contribution of current is required, the VGS of inactive pixels needs tobe kept to 100+100*n mV below the threshold voltage where 10̂n is thenumber of pixels in the row. Thus, for a 10000 row pixel array, VGSneeds to be kept to 500 mV below threshold. A typical 3.3V NMOStransistor has a VT of 600 mV. Therefore, VGS should be less than 100 mVfor inactive pixels. Assuming that the FG has a nominal voltage of 0Vwhen the row (R) and column (C) lines are at 0V, this condition is meteven as R and C couple to the FG. If the FG has a larger nominal voltagethan 0V (for example, due to the trapped charge), more bootstrapping isnecessary to cause the column line to reach a level within 100 mV of theFG. As long as the nominal FG voltage is sufficiently low, the secondcriteria for minimizing distortion current is not a limiting factor.Finally, enough bootstrapping is needed to produce a current on thecolumn line that matches the bleeding current so that the pixel canproduce a measurable voltage on the column line. If VG is nominally 0 v,then 700 mV is needed for bootstrapping. Therefore, for an NMOS with VTas large as 600 mV, the amount of bootstrapping required is simplylimited by the VT. In order to readout the pixel with margin, a goodtarget for bootstrapping is 1V. This leaves 300 mV of range forvariation. Achieving 1V of bootstrapping is practical within a 3.3Vsupply.

All the current from the column readout is distributed through the rowline. This causes significant droop in the voltage of the row line ifthe column current is also significant. The voltage droop affects thebootstrapping level but is not detrimental to the readout of the sourcefollower because variation in drain voltage has only a second ordereffect. Since pixels are read out with multiple samples, offsets arecanceled such that the droop does not affect the sensitivity of thepixels.

It should be noted that the same layout can be used for both sourcefollower readout and common source readout as long as optimizations arenot made for either. Only accommodations that need to be made are in thecolumn circuits. This makes for a flexible readout architecture andeither readout method may be used depending on the necessary signalrange. If the signal needs a high gain, the common source mode should beused. Otherwise, the source follower mode may be used.

FIG. 4 shows the source follower configuration of the 1T pixel accordingto one embodiment of the present invention. The source follower mode hasa buffered readout and operates in a voltage mode, and has a gain lessthan 1. As shown, the sole transistor 401 may be coupled to an inputvoltage Vi at its gate G and to a fixed voltage at its drain D. Thesource S of the transistor 401 may be grounded via a current sourceIsource. The output voltage Vo may be taken from the source of thetransistor 401. A coupling capacitance Cc may exist between the inputand the gate of the transistor 401, a parasitic capacitor Cgd may existbetween the gate G and the drain D of the transistor 401, and aparasitic capacitor Cgs may exist between the gate and the source S ofthe transistor 401.

The following analysis is given for the gain of the source followerreadout. Referring to FIG. 4, the gain of the circuit (G) may be definedas Vo/Vi. Using reference pixels the electrode of the system may beswept to measure the gain such that Vo/Vi=G. Using the measured value ofa parameter G, which is 0.65 in this example, the ratio of Cc to Cgd maybe determined. As will be discussed later, it is this ratio that willdetermine the gain in the common source mode. The input capacitance ofthe source follower is Ci=Cgd+Cgs(I−Asf), wherein Asf is the gain ofsource follower. Due to the body effect, Asf is approximately 0.85. Thecapacitive divider relating to the input voltage on the FET isCc/(Ci+Cc) and therefore, Cc/(Ci+Cc)=G/Asf. Since Cgs is about 3-5 timeslarger than Cgd and Asf is about 0.85, Ci is approximately 2Cgd.Therefore, Cc=2Cgd(G/(Asf−G)). In this example, the ratio of Cc to Cgdis about 6.5.

In one embodiment, the present invention obtains voltage gain by readingout with the common source configuration. It is desirable to achieveboth a reduction in pixel size as well as an increase in signal level.The present invention eliminates the ancillary transistors in otherpixel designs (e.g., 2T and 3T discussed below) and uses the source ofthe ISFET as the selection line to achieve both of these goals. Thecommon source mode is a gain mode and a current mode.

FIG. 5A shows a 1T common source ion sensitive pixel according to oneembodiment of the present invention. As shown, the pixel 500 may haveone and only one transistor 501, one and only one row line R and one andonly one column line C. The transistor 501 is shown as an n-channelMOSFET (NMOS) transistor in a p-type epitaxial substrate available usingstandard CMOS processes in this embodiment, although it may be ap-channel MOSFET as well. An NMOS device is typically preferred in usewith a P+ epi wafer that requires no front side bulk contacts.Technically a PMOS could be use with a N+ epi wafer, but thisconfiguration is not as commonly produced in standard CMOS processes.The row line R may be coupled to the source S of the transistor 501, andthe column line may be coupled to the drain D of the transistor 501. Therow selection is facilitated by switching on a path for the sourcevoltage, and the readout of the pixel is through the drain.

The schematic of an array of pixels with column readout switchesaccording to one embodiment of the present invention is shown in FIG. 6.The array 600 has four 1T common source pixels 601, 602, 603 and 604.The 1T pixel may be similar to the one shown in FIG. 5A. In thisexample, pixels are arranged into two rows and two columns. The drainsof pixels 601 and 602 are coupled to a column line C0, and the sourcesof pixels 601 and 602 are coupled to row lines R0 and R1 respectively.The drains of pixels 603 and 604 are coupled to a column line C1, andthe sources of pixels 603 and 604 are coupled to row lines R0 and R1respectively. A column readout switch 605 is coupled to the column lineC0 and a column readout switch 606 is coupled to the column line C1. Thecolumn readout switch 605 comprises a switch Sa, a switch Sb, a resistorR and a capacitor C_(w0). The column readout switch 606 comprises aswitch Sa, a switch Sb, a resistor R and a capacitor C_(w1). The switchSa may pull the voltage on the column line to a fixed voltage, forexample, to a 3.3V supply. When the column line switch Sb is open, thefinal value on the column line will be determined by the active rowsince the switch Sb, along with the capacitor C_(w0), acts as a sampleand hold circuit.

The pixel array can be loaded with a current source with finite outputresistance or another load device such as a resistor. Normally the rowselection lines will be held at an active high voltage VH. When a row isselected for readout, its row selection line is pulled low to VL. Thevalue of VL is set such that the nominal current level is about 1 uA. Ifthe FG has a value of 100 mV higher than the norm, 10 times this currentwill result on the column line. If the value of FG is 100 mV lower thanthe norm, the current will be 10 times lower. The settling time of thesignal on the column line will be signal dependent. The voltage gain isachieved with the selection of the value of R and it can be configurableto achieve programmable gain. For example, if R is 100 k ohms, then the100 mV, translates to 1V at the output.

The actual circuit is more complicated than just a simple common sourceamplifier because of the parasitic capacitance involved. Since the FGnode is not driven, but rather capacitively coupled to the output, thereis a feedback mechanism that limits the gain. This limit is roughlyequal to the total capacitance at the FG node to the gate to draincapacitance. This ratio may be about 3. It could be designed to achievehigher gain such as 10 times with careful mask operations to reducesource and drain extensions.

FIG. 7A shows the cross section of a 1T common source pixel according toone embodiment of the present invention. The transistor in the 1T pixelmay be formed using an n-channel FET device by having a drain D andsource S be formed using n-type implants within a p-type semiconductor.As shown, the transistor may have a floating gate G, the drain D and thesource S. The source S may be coupled to the row line R and the drain Dmay be coupled to the column line C. Lightly doped drain (LDD) regionsmay create a gate to source overlap capacitance Cgs and a gate to drainoverlap capacitance Cgd.

The overlap capacitance created by the LDD regions can be reduced byskipping the LDD implants at the drain for the device. FIG. 7B shows thecross section of a 1T common source pixel according to one embodiment ofthe present invention. FIG. 7B shows a drain node with a missing LDDregion. This missing region reduces the capacitance and increases gain.This can be achieved through masking out the LDD implants and can beimplemented in standard CMOS processing.

In the 1T pixel shown in FIG. 5A, since the source current must besupplied from the row selection line, variations in current due tovariations in signal will create variations in voltage. These variationscan distort the measurements. Therefore the row selection line should below resistance and the driver for that line should also supply a steadysource voltage independent of the current load. Where this is notpossible, the current can be supplied from the column line and a secondselection transistor can be added to form a 2T pixel for common sourceread out, as shown in FIG. 10A described below. Since the gain islimited by the parasitic overlap capacitance, it is expected that thebest load to use is a current source implemented with transistors ofhigh output resistance. In this case, relatively constant current willbe maintained in all devices since the gain is achieved throughcapacitor ratios. This makes the 1T configuration feasible since voltagevariation at the source is minimal, even with a single row selectionline that carries all the current.

The pixel in common source readout configuration is shown in FIG. 5B.The transistor forms an amplifier with negative voltage gain. Thisnegative voltage gain forms a natural feedback loop with the parasiticcapacitors in order to control the gain. The open loop gain of theamplifier is A=gm(ro), wherein gm is a transconductance. The value A istypically larger than 100 for a given bias condition and processtechnology. As shown in FIG. 5C, the common source equivalent circuithas a feedback capacitance Cgd, a coupling capacitance Cc, and Cgs.

Since A is large compared to the loop gain, the negative input terminalmay be considered as a virtual ground node and the gain of the circuitmay be determined as Vo/Vi=−Cc/Cgd. Since this ratio is known from theanalysis or measured values of the source follower configuration, thegain may be determined to be about 6.5. However compared to the sourcefollower, the gain is Vo/Vi=2/(Asf−G). In this example, a gain of 10 isrealized over the source follower configuration. A lower bound on thisgain is given by assuming that the input capacitance of the sourcefollower is solely due to Cgd and that the Asf is equal to 1. In thiscase the gain is about 3. Since neither of these conditions isrealistic, the gain is expected to always exceed this number. Thus, ifthe gain of the source follower configuration of a pixel is known, thegain of the common source configuration of this pixel is also known. Inaddition, the higher the gain, the more sensitive the pixel is. Thismakes the common source configuration preferable.

Flicker noise can be reduced by using a channel doping of the same typeas the minority carrier. For example, an NMOS with a n-type implantproduces a buried channel transistor. To shift the workfunction of thedevice, a P+ gate electrode can be used.

One-Transistor Pixel Array with Cascoded Column Circuit

One derivative of the one-transistor pixel allows for increasedprogrammable gain through a cascoded transistor enabled during readout.

Since the gain of the common source readout is limited by the Cgdcapacitance, as shown in FIG. 5B, lowering this capacitance can increasethe gain. FIG. 8 shows a common source pixel with a cascoded rowselection device. As shown, a transistor 801 may be added to a commonsource pixel, e.g., the circuit shown in FIG. 5B. The gate of thetransistor 801 may be coupled to a voltage Vb, and the source of thetransistor 801 may be coupled to the drain of the transistor 501. Theoutput voltage Vo may be taken from the drain of the transistor 801. Thecascode effectively removes the Cgd capacitance from the feedback loopand replaces it with Cds which is much smaller. Gain on the order of theloop gain is then achievable, which may exceed 100.

Higher gain and variable gain may be produced in the 1T configuration bybringing the cascode device outside the pixel to the column line. FIG. 9shows a one-transistor pixel array with cascoded column circuit. Thisallows high gain and yet still allows the pixel pitch to be minimizedwith only 1 transistor per pixel. The shown pixel array is a columnhaving a number of one-transistor pixels (e.g., 500) connected inseries, and has a cascode device at the base of the array. The cascodedevice may comprise a transistor 901. The gate of the transistor 901 maybe coupled to a bias voltage Vb, the source of the transistor 901 may becoupled to the drain of the transistor 501, and the drain of thetransistor 901 may be coupled to a fixed voltage via a current source.The output voltage Vo may be taken from the drain of the transistor 901.It should be understood that the array may have a number of columns.

In this case, the cascode forces the drain of the pixel to remain at afairly steady voltage over the range of inputs. This causes the pixel topush nearly all of the change in current through the cascode device atthe base of the array and into the current load. This reduces thenegative feedback from Cds, which would otherwise limit the gain. Giventhat the current load has infinite output resistance and there iseffectively no coupling capacitor to the FG node, the gain of the pixelis now −(gmlrO1+1)gm2rO2, wherein gml is the transconductance of thecascode device at the base of the column line and gm2 is thetransconductance of the pixel and rO1 and rO2 are the small signaloutput resistances as seen at the drain. The value of the outputresistance is determined by channel length modulation. Longer gatelengths produce higher output resistance because the effect of channellength modulation is minimized. Since this gain is so large, it can belimited and configured by variation of the current source outputresistance, which is shown as Radj in FIG. 9. This allows forprogrammable gain at the column level while maintaining a simple 1transistor pixel. The gain of the pixel is then set by −gm2RL, assumingthat the load resistance RL is much smaller than the output resistanceof the cascode configuration, where R_(L) is the adjusted value of Radj.The gain is now configurable and programmable within the range of 1 to100 or larger. For example, if the bias current is about 5 uA, thetransconductance of the pixel is about 50 uA/V, and a load resistance of20K ohms is needed for gain of 1. A gain of 10 is achieved with a 200Kohm load and gain of 100 with a 2M ohm load. There are many was toimplement the effect of the cascode device at the column line. The mainpurpose of the cascode, as shown in FIG. 901 as an NMOS transistor, isthat the column line is held to a potential that is largely independentof the current level in the pixel. A differential amplifier with highgain can be applied to maintain this condition more precisely. Thisapproach would be called gain-enhanced cascoding.

Various layout choices can be made to implement a 1 T and 2T transistor.In order to reduce the size of the pixel the source and drains ofadjacent pixels can be shared. In this way a single row selection lineenables 2 rows at a time. This reduces the row wiring: two columns arethen read out at once for a given column pitch. Such a scheme is shownin FIGS. 10A and 10B. As shown, a pixel array 1000 comprises transistors1001, 1002, 1003 and 1004 in a column. The source of 1001 is coupled toa row line R2, and the source of 1004 is coupled to a row line R0.Transistors 1001 and 1002 may form a mirror M1, and transistors 1003 and1004 may form a mirror M2. The drain of 1001 and 1002 are coupled to acolumn line CA, and the drain of 1003 and 1004 are coupled to a columnline CB.

In one embodiment, the cascoded device is gain-enhanced with adifferential amplifier in feedback to control a transistor thatmaintains a constant voltage on the column line.

Two-Transistor Pixel Array

In a pixel array, a row selection device may be used for selection andisolation. When a row selection line is activated, the row selectiondevice (a MOSFET) forms a channel due to the gate voltage exceeding athreshold voltage and acts like a switch. When the row selection isdeactivated, the channel is diminished. It is important to note that arow selection device never really completely turns “on” or “off”. Itonly approximates a switch. When the gate is substantially lower thanthe source of the row selection transistor, good isolation is achievedand the pixel with the active row selection can be read effectivelywithout input from deactivated pixels. With many rows in an array ofpixels, it is necessary to achieve a given level of isolation for eachrow selection device. That is, the requirements for the row selectiondevice depend on the number of rows.

FIG. 11 shows a two-transistor (2T) pixel according to one embodiment ofthe present invention. As shown, the 2T pixel 1100 comprises an ISFET1101 and a row selection device 1102. In the pixel 1100, the source ofthe ISFET 1101 is coupled to a column line Cb, the drain of the rowselection device 1102 is coupled to a column line Ct, and the drain ofthe ISFET 1101 is coupled to the source of the row selection device1102. The gate of the row selection device 1102 is coupled to a row lineR.

Both ISFET 1101 and the row selection device 1102 are shown as NMOS, butother types of transistors may be used as well. The 2T pixel 1100 isconfigured as the source follower readout mode, although 2T pixels maybe configured as the common source readout mode.

FIG. 12A to 12H illustrate more 2T pixel configurations according toembodiments of the present invention. In these Figures, “BE” stands for“with body effect”, i.e. the ISFET is body-effected because the bodyterminal is connected to the analog supply voltage or analog groundvoltage (depending on whether the ISFET transistor type is p-channel orn-channel MOS). The body effect is eliminated if the body terminal isconnected to the source terminal of the transistor. “PR” stands for“PMOS devices in reversed positions”, i.e. the positions of thep-channel ISFET and row selection device in the pixel circuit topologyhave been reversed (or switched around). “PNR” stands for “PMOS/NMOSdevices in reversed positions”, i.e. the positions of the p-channelISFET and n-channel row selection device in the pixel circuit topologyhave been reversed (or switched around).

FIG. 12A illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, both the ISFET and the row selection deviceSEL are p-channel MOS transistors, with the source terminal of the ISFETcoupled to the drain terminal of the row selection device. The drainterminal of the ISFET is connected to the analog ground voltage and thesource terminal of the row selection device is connected to a currentsource, which provides a bias current to the pixel. The output voltageVout is read out from the source terminal of the row selection device.

FIG. 12B illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, both the ISFET and the row selection deviceSEL are p-channel MOS transistors, with the source terminal of the ISFETconnected to the body terminal to eliminate the body effect, and alsoconnected to the drain terminal of the row selection device. The drainterminal of the ISFET is connected to the analog ground voltage and thesource terminal of the row selection device is connected to a currentsource, which provides a bias current to the pixel. The output voltageVout is read out from the source terminal of the row selection device.

FIG. 12C illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, both the ISFET and the row selection deviceSEL are p-channel MOS transistors, with the drain terminal of the ISFETconnected to the source terminal of the row selection device. The drainterminal of the row selection device is connected to the analog groundvoltage and the source terminal of the ISFET is connected to a currentsource. The output voltage Vout is read out from the source terminal ofthe ISFET.

FIG. 12D illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, both the ISFET and the row selection deviceSEL are p-channel MOS transistors, with the drain terminal of the ISFETconnected to the source terminal of the row selection device. The drainof the row selection terminal is connected to the analog ground voltageand the source terminal of the ISFET is connected to a current source,which provides a bias current to the pixel. The output voltage Vout isread out from the source terminal of the ISFET. The source terminal ofthe ISFET is connected to the body terminal to eliminate the bodyeffect.

FIG. 12E illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, the ISFET and the row selection device SELare p-channel and n-channel MOS transistors respectively, with theirsource terminals connected together. The drain terminal of the ISFET isconnected to the analog ground voltage and the drain of the rowselection device is connected to a current source, which provides a biascurrent to the pixel. The output voltage Vout is read out from the drainterminal of the row selection device.

FIG. 12F illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, the ISFET and the row selection device SELare p-channel and n-channel MOS transistors respectively, with theirsource terminals connected together. The drain terminal of the ISFET isconnected to the analog ground voltage and the drain of the rowselection device is connected to a current source, which provides a biascurrent to the pixel. The output voltage Vout is read out from the drainterminal of the row selection device. The source terminal of the ISFETis connected to the body terminal to eliminate the body effect.

FIG. 12G illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, the ISFET and the row selection device SELare p-channel and n-channel MOS transistors respectively, with theirdrain terminals coupled together. The source terminal of the rowselection device is connected to the analog ground voltage and thesource terminal of the ISFET is connected to a current source, whichprovides a bias current to the pixel. The output voltage Vout is readout from the source terminal of the ISFET.

FIG. 12H illustrates a 2T pixel, according to one embodiment of thepresent invention. As shown, the ISFET and the row selection device SELare p-channel and n-channel MOS transistors respectively, with theirdrain terminals coupled together. The source terminal of the rowselection device is connected to the analog ground voltage and thesource terminal of the ISFET is connected to a current source, whichprovides a bias current to the pixel. The output voltage Vout is readout from the source terminal of the ISFET. The source terminal of theISFET is connected to the body terminal to eliminate the body effect.

FIGS. 13A to 13D illustrate common source 2T cell configurationsaccording to embodiments of the present invention. In FIGS. 13A and 13B,both the ISFET and the row selection device are n-channel MOStransistors, and in FIGS. 13C and 13D, both the ISFET and the rowselection device are p-channel MOS transistors.

In FIG. 13A, the source terminal of the ISFET is connected to the analogground supply and the drain terminal of the row selection device isconnected to a current source, which provides a bias current to thepixel. The source terminal of the row selection device and the drainterminal of the ISFET are connected together. The output voltage Vout isread out from the drain terminal of the row selection device.

In FIG. 13B, the source terminal of the row selection device isconnected to the analog ground supply and the drain terminal of theISFET is connected to a current source, which provides a bias current tothe pixel. The drain terminal of the row selection device and the sourceterminal of the ISFET are connected together. The output voltage Vout isread out from the drain terminal of the ISFET.

In FIG. 13C, the source terminal of the ISFET is connected to the analogsupply voltage, and the drain terminal of the row selection device isconnected to a current source, which provides a bias current to thepixel. The source terminal of the row selection device and the drainterminal of the ISFET are connected together. The output voltage Vout isread out from the drain terminal of the row selection device.

In FIG. 13D, the source terminal of the row selection device isconnected to the analog supply voltage, and the drain terminal of theISFET is connected to a current source, which provides a bias current tothe pixel. The source terminal of the ISFET and the drain terminal ofthe row selection terminal are connected together. The output voltageVout is read out from the drain terminal of the ISFET.

FIG. 14A shows a 2T pixel array according to one embodiment of thepresent invention. For illustrative purposes, eight 2T pixels are shownarranged into two columns, though the 2T pixel array 1400 could extendto an array of any size of 2T pixels. Each column pitch contains threecolumn lines cb[0], ct[0] and cb[1], The row lines rs[0], rs[1], rs[2]and rs[3], connect to all columns in parallel. A row selection device1401RS and an ISFET 1401IS may form one 2T pixel, with the source of1401IS connected to the drain of 1401RS. The source of 1401RS isconnected to the column line cb[0], and the drain of 1401IS is connectedto the column line ct[0]. The gate of 1401RS is connected to the rowline rs[0). This pixel is mirrored in a pixel comprising 1402IS and1402RS, with drains of 1401IS and 1402IS connected to the column linect[0], and the gate of 1402RS connected to the row line rs[1]. The pixelcomprising 1402IS and 1402RS is mirrored in a pixel comprising 1403ISand 1403RS, with the source of 1402RS and 1403RS connected to the rowline cb[1], and the gate of 1403RS coupled to the row line rs[2]. Thepixel comprising 1403IS and 1403RS is mirrored in a pixel comprising1404IS and 1404RS, with the drains of 1403IS and 140415 connected to therow line ct[0], the gate of 1404RS coupled to the row line rs[3], andthe source of 1404RS coupled to the column line cb[0]. In the embodimentshown in FIG. 14, each of the IS devices is an ISFET and each of the RSdevices is a row select device.

The right column, including a pixel consisting of 1405RS and 1405IS, apixel consisting of 1406RS and 1406IS, a pixel consisting of 1407RS and1407IS, and a pixel consisting of 1408RS and 1408IS, is coupled tocolumn traces cb[2], ct[1], and cb[3] in substantially the same manneras described above.

FIGS. 14B and 14C show a layout for a 2×2 2T pixel array according to anembodiment of the present invention. The 2×2 2T pixel array may be partof the pixel array 1400. FIG. 14B shows that polysilicon gates for1401RS, 1401IS, 1402RS and 1402IS may be placed on top of a continuousdiffusion layer 1410 and polysilicon gates for 1405RS, 1405IS, 1406RSand 1406IS may be placed on top of a continuous diffusion layer 1412. Inone embodiment, the continuous diffusion layers 1410 and 1412 may runfrom the top of the pixel array to the bottom of the pixel array. Thatis, the diffusion layer may have no discontinuities in the pixel array.

FIG. 14C shows where microwells for ISFETs 1401IS, 1402IS, 1405IS and1406IS may be placed. The microwells may be used to hold analytesolutions that may be analyzed by the ISFETs. As shown in FIG. 14C, inone embodiment, the microwells may each have a hexagonal shape andstacked like a honeycomb. Further, in one embodiment, the contact may beplaced directly on top of the gate structure. That is, the ISFETs mayhave a contact landed on polysilicon gate over thin oxide.

The pixel array 1400 has high density because of continuous diffusion,shared contacts, mirrored pixels, and one ct (column top) line and 2 cb(column bottom) line per physical column. A global bulk contact may beimplemented by using a P+ wafer with P− epitaxy region.

The arrangement of pixel array 1400 provides for high speed operation.Row lines rs[0] and rs[1] are selected together and readout throughcb[0] and cb[1]. This leads to a 4 times faster readout due to twice thenumber of pixels enabled for a single readout and half the parasiticload of a continuous array, allowing each column to settle twice asfast. In an embodiment, the full array is separated into a top half anda bottom half. This leads to another 4 times faster readout time due totwice the number of pixels readout at a time (both out the top and thebottom) and half the parasitic load of a continuous array. Thus, thetotal increase in speed over a single row selected continuous array is16 times.

In an embodiment, both top and bottom halves of the pixel array may beenabled at the same time during readout. This can allow a multiplexingof readout between the top half and the bottom half. For example, onehalf can be doing a “wash” (e.g., flushing out reactants from the wellsover the pixel devices) and the other half can be performing thereadout. Once the other half is read, the readout for the two halves isswitched.

In an embodiment, a 2T pixel design can incorporate twochemically-sensitive transistors (e.g., ISFETs) rather than onechemically-sensitive transistor and one row select device as describedwith respect to FIGS. 11-14. Both chemically-sensitive transistors, orISFETs, can be NMOS or PMOS device and configured in a source followeror common source readout mode. Possible uses of such a 2T pixel may bewhere the first chemically-sensitive transistor has a differentsensitivity to a particular analyte to that of the secondchemically-sensitive transistor, allowing a local and in-pixeldifferential measurement to be made. Alternatively, bothchemically-sensitive transistors may have the same sensitivity to aparticular analyte, allowing a local and in-pixel average measurement tobe made. These are among two examples of potential uses for thisembodiment, and based on the description herein, a person of ordinaryskill in the art will recognize other uses for the 2T pixel design thatincorporate two chemically-sensitive transistors (e.g., ISFETs).

In one embodiment, a column circuit allows column lines to be swapped toa sampling circuit such that either source-side or drain-side rowselection can be made in either source follower mode or common sourcemode.

Capacitive Charge Pump

One or more charge pumps may be used to amplify the output voltage froma chemically-sensitive pixel that comprises one or more transistors,such as those described above.

One or more charge pumps may be used to amplify the output voltage froma chemically-sensitive pixel that comprises one or more transistors,such as those described above.

FIG. 15 shows a capacitive charge pump with a two times voltage gainaccording to one embodiment of the present invention. A charge pump 1500may comprise φ1 switches 1501, 1502, 1503 and 1504, φ2 switches 1505 and1506, and capacitors 1507 and 1508. Vref1 and Vref2 are set to obtainthe desired DC offset of the output signal, and both are chosen to avoidsaturation of the output during the boost phase. The operation of thecharge pump may be controlled by timing signals, which may be providedby a timing circuit.

At time t0, all switches are off.

At time t1, φ1 switches 1501, 1502, 1503 and 1504 are turned on. Thetrack phase may start. An input voltage Vin, which may be from an ionsensitive pixel, may start to charge capacitors 1507 and 1508.

At time t2, φ1 switches 1501, 1502, 1503 and 1504 are turned off, andcapacitors 1507 and 1508 are charged to Vin−Vref1.

At time t3, φ2 switches 1505 and 1506 are turned on, while φ1 switches1501, 1502, 1503 and 1504 remain off. The boost phase may start. Thecapacitor 1507 may start to discharge through the capacitor 1508. Sincethe capacitors are in parallel during the track phase and in seriesduring the boost phase, and the total capacitance is halved during theboost phase while the total charge remains fixed, the voltage over thetotal capacitance must double, making Vout approximately two times Vin.

A source follower SF may be used to decouple the gain circuit from thefollowing stage.

The charge pump 1500 may provide a two times gain without a noisyamplifier to provide a virtual ground.

FIG. 16 shows a charge pump according to an embodiment of the presentinvention.

At time t0, all switches are off.

At time t1, φ1 switches 1501, 1502, 1503, 1504, 1601 and 1602 are turnedon. The track phase may start. An input voltage Vin, which may be froman ion sensitive pixel, may start to charge capacitors 1507, 1508 and1604.

At time t2, φ1 switches 1501, 1502, 1503, 1504, 1601 and 1602 are turnedoff, and capacitors 1507, 1508 and 1604 are charged to Vin−Vref1.

At time t3, φ2 switches 1505 and 1603 are turned on, while φ1 switches1501, 1502, 1503, 1504, 1601 and 1602 remain off. The boost phase maystart. The capacitor 1507 may start to discharge through the capacitors1508 and 1604, and the capacitor 1508 may start to discharge through thecapacitor 1604. Since the capacitors are in parallel during the trackphase and in series during the boost phase, and the total capacitance isdivided by three during the boost phase while the total charge remainsfixed, the voltage over the total capacitance must triple, making Voutapproximately three times Vin.

FIG. 17 shows an embodiment of a charge pump according to an embodimentof the present invention. Two charge pumps 1500 shown in FIG. 15 areconnected in series, enabling gain pipelining and amplifying inputvoltage Vin by a factor of four.

Additional series charge pumps can be added to increase the gainfurther. In a multi-stage charge pump, the capacitor values do not haveto be the same size from stage to stage. It can be observed that thetotal area consumed by capacitors increases with the square of the gain.Although this feature may, in some cases, be undesirable with respect toarea usage, power consumption, and throughput, the charge pump can beused without these penalties when the total noise produced by the ionsensitive pixel and associated fluidic noise is larger than the chargepump KT/C noise when a reasonable capacitor size is used.

FIG. 18 shows an embodiment of a charge pump according to an embodimentof the present invention. A feedback path including a source followerSFP and a switch φfb is added to the charge pump 1500, feeding theoutput Vout back to the input of the charge pump.

At time t0, all switches are off.

At time t1, a switch φsp is on, providing an input voltage Vin to theinput of the charge pump 1500.

From time t2 to time t5, the charge pump 1500 operates to push theoutput voltage Vout to 2(Vin−Vref1), as described before with referenceto FIG. 15.

From time t6 to t7, the switch φfb is on, feeding the output voltage2(Vin−Vref1). back to the input of the charge pump 1500, and the firstcycle ends.

During the second cycle, the charge pump 1500 amplifies the outputvoltage by 2(2(Vin−Vref1)). The process repeats, with the output beingamplified during each cycle.

CCD-Based Multi-Transistor Active Pixel Sensor Array

An ion sensitive MOS electrode is charge coupled to adjacent electrodesto facilitate both confinement and isolation of carriers. Measurementsof ion concentration are made by discrete charge packets produced ateach pixel and confined by potential barriers and wells. The ionsensitive electrode can act as either a barrier level or as a potentialwell. Working in the charge domain provides several benefits, includingbut not limited to: 1) increased signal level and improved signal tonoise through the accumulation of multiple charge packets within eachpixel, 2) better threshold matching of the MOS sensing and referencestructures, 3) reduction in flicker noise, and 4) global-snap shotoperation.

A floating electrode is used to detect ions in close proximity to theelectrode. The electrode is charge coupled to other electrodes and toother transistors to form a pixel that can be placed into an array foraddressable readout. It is possible to obtain gain by accumulatingcharge into another electrode or onto a floating diffusion (FD) node ordirectly onto the column line. It is desirable to achieve both areduction in pixel size as well as increase in signal level. To reducepixel size, ancillary transistors may be eliminated and a charge storagenode with certain activation and deactivation sequences may be used.

The ion sensitive (IS) accumulation pixel contains some of the followingconcepts:

1. Electrodes are charge coupled to the IS electrode;

2. A source of carriers (electrons or holes) for charge packets;

3. A reference electrode to act as a barrier or a well for the chargepackets;

4. A floating diffusion node for charge to voltage conversion;

5. Ancillary transistors to provide buffering and isolation foraddressable readout; and

6. Sequences to eliminate some or all ancillary transistors depending onthe application.

The basic IS accumulation pixel is shown in FIG. 19. Charge accumulationcan occur either locally at the time of readout or globally during aseparate integration time. The embodiment shown in FIG. 19 is a threetransistor three electrode (3T3E) pixel. The three transistors include areset transistor RT, a source follower 1901 and a row selectiontransistor RS, and the three electrodes include an electrode VS, anelectrode VR, and an ion sensitive electrode 1902. The pixel alsoincludes a transfer gate TX. It is also possible to configure the ISaccumulation pixel with additional elements to allow simultaneousaccumulation and readout. This can be done, for example, by adding 2more electrodes to pipeline the process. In the basic configuration,charge is accumulated onto the floating diffusion node that is connectedto the source of the reset (RT) control gate. In a rolling shutteroperation, the floating diffusion (FD) is reset to CD=VDD. The row isthen selected and readout through the source follower enabled by rowselection (RS). Next, charge is accumulated onto the FD node whichdischarged the parasitic capacitor. A second sample is then taken. Thedifference between the samples represents the ion concentration. Thesamples are correlated and taken relatively quickly in time. Therefore,the thermal noise of the readout circuit is eliminated and the 1/f noiseis reduced. To operate in a global shutter mode, all FD nodes aresimultaneously reset to VDD. Then charge is accumulated on each isolatedFD node. After accumulation, each row is selected by enabling the RSgate. The signal value is readout on the column line with a load on thesource follower. Next the pixel is reset and sampled again. Thedifference between the samples represents the ion concentration. The 1/fnoise is reduced through the double sampling. However, the thermal resetnoise is not eliminated because the reset value is uncorrelated in time.The thermal noise can be reduced by half the power by following thereset operation with a subthreshold reset before sampling. In general,the thermal noise is low compared to the signal due to the chargeaccumulation. A correlated reset scheme with global shutter is availablein other configurations.

The basic charge accumulation scheme is shown in FIG. 20 using thesurface potential diagrams. Only the electrodes are shown since thetransistors are only used for readout. In each of these sequences,increasing potential is pointing down as is conventional to showpotential wells containing electrons. Four cycles of charge accumulationare shown in FIG. 20A-P. First, all charge is removed from the channelunder the IS electrode and the channels are fully depleted using a highpotential on FD (A). Next, the TX gate transitions to a low potentialwhich creates the confinement barrier (B). A fill and spill operation isused to produce a charge packet proportional to the ion concentration atthe IS electrode (C-D). In the next cycle, this charge packet istransferred to the FD node which discharges due to the electrons. Thediagram shows electrons accumulating on the FD node, but the voltage isactually decreasing. After many cycles, as shown in FIG. 20E-P, thesignal to noise ratio is improved and the signal can be read out withgain. Hundreds to millions of cycles can be used to amplify the signal.

In alternative embodiments, the order of electrodes may be switched,and/or the IS electrode may be used as the barrier rather than the well.Transistors may be added to this accumulation line to enable a largearray of pixels. The ancillary transistors are used to increase speed.However, it should be noted that no transistors are necessary to enablea full pixel array of the accumulation line. Instead, an array can bepartitioned such that no transistors are needed. In an embodiment, theFD nodes are connected to the column line. Before a pixel is read out,the column line is reset to VDD. Then a row is selected by accumulatingcharge for that row directly onto the column line. After many cycles,the column discharges to a value directly proportional to the ionconcentration. Since the capacitance of the column line depends on thetotal number of rows, the amount of accumulation required, depends onthe number of rows. The array can be partitioned into sub arrays to maketiming scalable. For example, every 100 rows can contain a local sourcefollower buffer that is then connected to a global array. Thishierarchical approach can be used in general with all readout schemes tomake massive arrays of pixels with fast readout.

Due to the thermal activity of carriers, charge packets cannot begenerated without noise. Each fill and spill operation produces chargeerror proportional to KTC (thermal noise in the floating diffusioncapacitor), where C is equal to Cox times the area of the ion sensitiveelectrode. During the fill operation charge can flow freely between thesource of electrons and the confinement well. However, during the spilloperation, the device enters the subthreshold mode and carriers move bydiffusion, mainly in only one direction, which results in half of thethermal noise of a resistive channel. The total noise in electrons foreach charge packet is therefore sqrt(KTC/2)/q where q represents thecharge of one electron in coulombs (1.6×10e-19). The signal in electronsis equal to VC/q. The signal to noise ratio after n cycles is equal toV*sqrt(2nC/KT). Note that the signal to noise ratio improves by thesquare root of the number of cycles of accumulation. For small signallevels, the amount of accumulation will be limited to the thresholdmismatch between the VR reference electrode and the ion sensitiveelectrode. Since there is a reference electrode in every pixel and theelectrodes are charge coupled, the relative threshold mismatch betweeneach pair of electrodes is small. Assuming, this difference is about 1mV, over 1000 accumulation cycles should be feasible, thereby improvingthe signal to noise by more than 30 times. By way of example, if thesignal is 1 mV and the electrode area is 1 square micron withCox=5fF/um̂2, the signal to noise ratio after 1000 cycles is 50 to 1.Since the signal level then reaches 1 V, it is expected that no othernoise source is relevant. For clarity, the dominant noise is simply thecharge packet thermal noise which is well known.

FIGS. 21 and 22 show the IS accumulation pixel with only 2 transistors.The selection transistor is eliminated by using a deactivation sequenceafter a row is read out. To deactivate, the FD node is discharged, whichreduces the potential of the FD node and disables the source followerfor that row. The surface potential diagrams for the pixel of FIG. 22are shown in FIG. 23.

FIG. 24 shows the IS accumulation pixel with 2 transistors and 4electrodes. This pixel produces the fill and spill charge packets andreadout all at the same FD node. The 4th electrode allows global shutteroperation and correlated double sampling. For faster readout, singlesampling can be used if charge accumulation sufficiently reduces the 1/fnoise contribution. FIG. 25 shows the surface potential diagrams for thebasic operation of the pixel of FIG. 24.

FIG. 26 shows an IS accumulation pixel with 1 transistor and 3electrodes. The channel can be depleted and supplied from the same node.This pixel depends on charge coupling, and signal range is lower thansignal range for the other pixels.

Several design permutations are available depending on the desired modeof operation. The CCD channels are surface mode and are built instandard CMOS technology preferably below 0.13 um. Extra implants can beadded to avoid surface trapping and other defects. A channel stop andchannel can be formed from donor and acceptor impurity implants. Thechannel can be made of multiple implants to produce a potential profileoptimal for the mode of operation.

FIG. 27 shows an embodiment of a three transistor (3T) active pixelsensor. The three transistors are a reset transistor 2701, a sourcefollower 2702 and a row selection switch 2703. The reset transistor 2701has a gate controlled by a reset signal RST, a source coupled to thefloating diffusion (FD) of a pixel, and a drain connected to a fixedvoltage. The source follower 2702 has its gate connected to the sourceof the reset transistor 2701, and its drain connected to a fixedvoltage. A row selection transistor 2703 has its gate connected to a rowline, its drain connected to a fixed voltage and its source connected toa column. Other electrodes interacting with the pixel includes atransfer gate TG, an ion selective electrode ISE, an input control gateICG, and an input diffusion ID. These three elements form charge coupledelectrodes that are operated in an identical way to VS, VR, and TX inFIG. 19.

FIG. 28 shows an alternate embodiment of a 3T active pixel sensor. Thedifference between the sensor in FIG. 28 and the sensor shown in FIG. 27is that the sensor 2800 has a second input control gate ICG2, whichallows more control over the potential barrier near the ion-sensitiveelectrode.

FIG. 29 shows an embodiment of a 3T active pixel sensor with a sampleand hold circuit, which may be used to eliminate signal variations. Asshown, the gate of the row selection transistor 2703 is controlled by aRowSelm signal provided by a row selection shift register. The source ofthe row selection transistor 2703 is coupled to a current sink ISink2902 and a column buffer 2903. The current sink ISink 2902 may be biasedby a voltage VB1 and the column buffer, which may be an amplifier, maybe biased by a voltage VB2.

The sample and hold circuit 2901 may include a switch SH, a switch CAL,a capacitor Csh, and an amplifier Amp. The switch SH's input is coupledto the output of the column buffer 2903, and its output is coupled to avoltage VREF through the switch CAL, the upper part of the capacitorCsh, and the input of the amplifier Amp. The amplifier is biased by avoltage VB2. The output of the amplifier is coupled to a switch 2904controlled by a signal ColSeln from a column selection shift register.The output of the switch 2904 is buffered by an output buffer 2905before reaching the output terminal Vout. The output buffer is biased bya voltage VB3.

FIG. 30 shows an embodiment of a 3T active pixel sensor with acorrelated double sampling circuit. The most significant differencebetween the sensor in FIG. 30 and that in FIG. 29 is that the formeruses a correlated double sampling circuit 3001 to measure the signalfrom the column buffer 2903. An amplifier in the correlated doublesampling circuit 3001 receives at its first input the output of thecolumn buffer 2903 via a switch SH, and a capacitor Cin. The amplifierreceives a reference voltage VREF at its second input, and is biased bythe voltage VB2. A reset switch RST and a capacitor Cf are coupled inparallel with the amplifier.

FIG. 31 shows an embodiment of a 2.5T active pixel sensor used for afour pixel array. Each of the pixels has its own transfer transistorTX1, TX2, TX3 and TX4 and its own reset transistor. The drain of eachtransfer transistor is coupled to the source of the reset transistor inthe same pixel, and the source of each transfer transistor is coupled tothe gate of the source follower.

FIG. 32 shows an embodiment of a 1.75T active pixel sensor for a fourpixel array. Each of the pixels has its own transfer transistor. Thesource of each transfer transistor is coupled to the floating diffusionof the same pixel, and the drain of each transfer transistor is coupledto the drain of the reset transistor RST of the sensor.

Array Column Integrator

The described embodiments may provide a chemical detection circuit withan improved signal-to-noise ratio. The chemical detection circuit mayinclude a current source, a chemical detection pixel, an amplifier and acapacitor. The chemical detection pixel may comprise achemically-sensitive transistor that may have first and second terminalsand a row-select switch connected between the current source andchemically-sensitive transistor. The amplifier may have a first inputand a second input, with the first input connected to an output of thechemically-sensitive transistor via a switch and the second inputconnected to an offset voltage. The capacitor may be connected betweenan output of the amplifier and the first input of the amplifier. Thecapacitor and amplifier may form an integrator and may be shared by acolumn of chemical detection pixels.

Some embodiments may also provide a chemical detection circuit with animproved signal-to-noise ratio. The chemical detection circuit mayinclude a plurality of columns of chemical detection pixels. Each columnof chemical detection pixels may comprise a current source, a pluralityof chemical detection pixels, an amplifier and a capacitor. Eachchemical detection pixel may comprise a chemical-sensitive transistorthat may have first and second terminals and a row-select switchconnected between the current source and chemically-sensitivetransistor. The amplifier may have a first input and a second input,with the first input connected to an output of each chemically-sensitivetransistor via a switch and the second input connected to an offsetvoltage. The capacitor may be connected between an output of theamplifier and the first input of the amplifier. The capacitor andamplifier may form an integrator that is shared by a column of chemicaldetection pixels.

Other embodiments may provide a method to generate an output signal froma chemical detection circuit. The method may comprise selecting achemical detection pixel from a column of chemical detection pixels forreadout, integrating a readout current from the chemical detection pixelto an integrator, and reading out an output voltage of the integrator.

FIG. 33 illustrates a block diagram of a chemical detection circuit 3300according to an embodiment of the present invention. The chemicaldetection circuit 3300 may comprise a plurality of chemical detectionpixels 3302.1-3302.N, a current source 3308, an amplifier 3310, anoffset voltage V_(sd) 3314, a capacitor C_(int) 3312, and three switches3316, 3318 and 3320. Each chemical detection pixel (e.g., 3302.1, . . ., or 3302.N) may comprise a chemically-sensitive transistor (e.g.,3304.1, . . . , or 3304.N, respectively) and a row-select switch (e.g.,3306.1, . . . , or 3306.N, respectively). The amplifier 3310 may have afirst input terminal coupled to an output of the current source 3308 anda second input terminal coupled to the offset voltage V_(sd) 3314. Thecapacitor C_(int) 3312 may have a first side coupled to the first inputterminal of the amplifier 3310 and a second side coupled to an outputterminal of the amplifier 3310 via the switch 3318. The switch 3316 maybe coupled between the first side of the capacitor C_(int) 3312 and theoutput terminal of the amplifier 3310. The switch 3320 may be coupledbetween the second side of the capacitor C_(int) 3312 and ground. In oneembodiment, the plurality of chemical detection pixels 3302.1 to 3302.Nmay form a column of chemical detection pixels. The capacitor C_(int)3312 may be configured as a negative feed back loop for the amplifier3310 and thus, the capacitor C_(int) 3312 and amplifier 3310 may form anintegrator for the column of chemical detection pixels. In oneembodiment, the integrator may be shared by all chemical detectionpixels of the column and may be referred to as a column integrator.

Each chemically-sensitive transistor may have a gate terminal that maybe covered by a passivation layer. The gate terminal may have a floatinggate structure sandwiched between a gate oxide and a passivation layer(e.g., floating gate G in FIG. 2). During operation, the passivationlayer may be exposed to an analyte solution to be analyzed. Eachchemically-sensitive transistor 3304.1˜3304.N may further have a firstterminal connected to a first side of a respective row-select switch3306.1˜3306.N and a second terminal connected to ground. For example, asshown in FIG. 33, the transistor 3304.1 may be a PMOS with a firstterminal (e.g., the source) connected to a first side of the row-selectswitch 3306.1 and a second side (e.g., the drain) connected to ground.Each row-select switch (e.g., 3306.1, . . . , or 3306.N) of eachchemical detection pixel may have a second side connected to the currentsource 3308. The second side of each row-select switch may also becoupled to the first input of the amplifier 3310.

In one embodiment, the chemical detection circuit 3300 may be configuredso that each of the chemically-sensitive transistors (e.g., 3304.1, . .. , or 3304.N) may work in a current-mode. That is, each of thechemically-sensitive transistors may work as a transconductanceamplifier. The ion-concentration of analyte being measured by thechemically-sensitive transistor may be detected by a current output. Inone embodiment, each chemically-sensitive transistor 3304.1 to 3304.Nmay be an ion-sensitive field effect transistor (ISFET) and eachrow-select switch 3306.1 to 3306.N may also be a transistor.

During operation, when one chemical detection pixel is selected, thecorresponding row-select switch may be closed. For example, as shown inFIG. 33, the chemical detection pixel 3302.1 may be selected, and thusthe row-select switch 3306.1 may be closed. The current source 3308 mayprovide a DC bias current I_(dc) to the selected chemically-sensitivetransistor 3304.1. The signal current I_(sig) resulting from gatevoltage change of the chemically-sensitive transistor 3304.1 may beintegrated onto the capacitor C_(int) 3312 and an output signal of theamplifier 3310 may be read out as V_(out). The offset voltage V_(sd)3314 to the second input of the amplifier 3310 may provide thesource-to-drain voltage V_(sd) for the chemically-sensitive transistorto operate.

Each measurement operation may comprise two phases. The first phase ofoperation may be an integration phase and the second phase of operationmay be a clear phase to clear charges. During the first phase ofoperation, the switch 3318 may be closed and switches 3316 and 3320 maybe left open. After the output signal Vout is read out, the operationmay enter the second phase, during which the switches 3316 and 3320 maybe closed and the switch 3318 may be left open to clear out the chargesaccumulated on the capacitor C_(int) 3312. In one embodiment, acorrelated-double-sampling (CDS) scheme may be implemented by closingswitch 3320 during the second phase. This may allow the inherent offsetvoltage of the amplifier 3310 to be stored on the capacitor C_(int)3312.

In one embodiment, the current source 3308 may be a programmable currentsource attached to each column to provide a DC bias current I_(dc),which may be relatively large. In this configuration, the bias currentI_(dc) will not integrate onto the capacitor C_(int) 3312 and thus theintegrator may avoid premature saturation. Amplification level may bederived from the C_(int) value and duration of integration.

Further, in one embodiment, the output signal Vout may be converted intoa digital signal by an ADC. For example, the charging signal currentI_(sig) may be digitized using a single-slope integration ADC such thata counter may increment (counting a number) until the integrator outputvoltage crosses some threshold as defined by a comparator. When thesingle-slope integration ADC is used, calibration may be performed todetermine an absolute value of the capacitor C_(int) 3312.Alternatively, a “dual-slope integrating ADC” may be used that uses afixed integration period followed by a variable discharge period. Inother embodiments, the output signal Vout may be converted into adigital signal by other known analog-to-digital conversion techniques.

In one embodiment, integration of current response of thechemically-sensitive transistor may provide a better signal-to-noiseratio (SNR) than measurement of instantaneous voltage output of achemically-sensitive transistor.

In one or more embodiments, it may be hard to completely cancel the DCcurrent of the chemical sensitive transistor using the current source3308. Therefore, in one embodiment, the size of the capacitor may belimited to a certain size. In another embodiment, the duration ofintegration time may be limited to, for example, 1 μs. If theintegration time is limited, a dual-slope ADC with a much slowerdischarge phase may be used to convert the output voltage Vout to adigital output.

FIG. 34 illustrates a block diagram of another chemical detectioncircuit 3400 according to an embodiment of the present invention. Thechemical detection circuit 3400 may comprise a plurality of chemicaldetection pixels 3402.1-3402.N, a current source 3408, an amplifier3410, a resistor 3424, an offset voltage V_(set) 3414, a capacitorC_(int) 3412, and three switches 3416, 3418 and 3420. Each chemicaldetection pixel (e.g., 3402.1, . . . , or 3402.N) may comprise achemically-sensitive transistor (e.g., 3404.1, . . . , or 3404.N,respectively), a row-select switch (e.g., 3406.1, . . . , or 3406.N,respectively) and an output switch (e.g., 3422.1, . . . , 3422.N). Theamplifier 3410 may have a first input terminal coupled to the outputswitches of the chemical detection pixels so that when a chemicaldetection pixel is selected, its output switch may be closed to generatean output signal for the first input terminal of the amplifier 3410. Theamplifier 3410 may also have a second input terminal coupled to theoffset voltage V_(set) 3414. The capacitor C_(int) 3412 may have a firstside coupled to the first input terminal of the amplifier 3410 and asecond side coupled to an output terminal of the amplifier 3410 via theswitch 3418. The switch 3416 may be coupled between the first side ofthe capacitor C_(int) 3412 and the output terminal of the amplifier3410. The switch 3420 may be coupled between the second side of thecapacitor C_(int) 3412 and ground. In one embodiment, the plurality ofchemical detection pixels 3402.1 to 3402.N may form a column of chemicaldetection pixels. The capacitor C_(int) 3412 may be configured as anegative feedback loop for the amplifier 3410 and thus, the capacitorC_(int) 3412 and amplifier 3410 may form an integrator for the column ofchemical detection pixels. The integrator may be shared by all chemicaldetection pixels of the column and may be referred to as a columnintegrator.

Each chemically-sensitive transistor 3404.1˜3404.N may have a gatestructure similar to that of the chemically-sensitive transistor3302.1˜3302.N. Each chemically-sensitive transistor 3404.1˜3404.N mayfurther have a first terminal connected to a first side of a respectiverow-select switch 3406.1˜3406.N and a first side of a respective outputswitch 3422.1˜3422.N. Each chemically-sensitive transistor 3404.1˜3404.Nmay also have a second terminal connected to ground. For example, asshown in FIG. 34, the transistor 3404.1 may be a PMOS with a firstterminal (e.g., the source) connected to a first side of the row-selectswitch 3406.1 and a first side of the output switch 3422.1. Further, thetransistor 3404.1 may also have a second side (e.g., the drain)connected to ground. Each row-select switch (e.g., 3406.1, . . . , or3406.N) of each chemical detection pixel 3402.1˜3402.N may have a secondside connected to the current source 3408. The second side of eachoutput switch 3422.1˜3422.N may also be coupled to the first input ofthe amplifier 3410 via the resistor 3424.

In one embodiment, the chemical detection circuit 3400 may be configuredthat each of the chemically-sensitive transistors (e.g., 3404.1, . . . ,or 3404.N) may work in a voltage-mode. That is, during operation, eachof the chemically-sensitive transistors may work as a voltage amplifier.The ion concentration of analyte being measured by thechemically-sensitive transistor may be detected by a voltage level atthe output. When one chemical detection pixel is selected, thecorresponding row-select and output switches may be closed. The offsetvoltage V_(set) may set an appropriate voltage between the virtualground (e.g., the first terminal or negative terminal) of the amplifier3410 and the output of the selected chemically-sensitive transistor. Forexample, as shown in FIG. 34, the chemical detection pixel 3402.1 may beselected, and thus the row-select switch 3406.1 and output switch 3422.1may be closed. The current source 3408 may provide a current I_(ss) tothe selected chemically-sensitive transistor 3404.1. The resistor 3424may be used to convert an output voltage at the selectedchemically-sensitive transistor to a charging current I_(is) to beintegrated onto the capacitor C_(int) 3412. An output signal of theamplifier 3410 may be read out as V_(out).

Similar to operation of the chemical detection circuit 3300, theoperation of the chemical detection circuit 3400 may have an integrationphase and a clear phase to clear charges. During the integration phase,the switch 3420 may be closed and switches 3416 and 3420 may be leftopen. After the output signal Vout is read out, the operation may enterthe second phase, during which the switches 3416 and 3420 may be closedand the switch 3418 may be left open to clear out the chargesaccumulated on the capacitor C_(int) 3412.

In one embodiment, each chemically-sensitive transistor 3404.1 to 3404.Nmay be an ion-sensitive field effect transistor (ISFET) and eachrow-select switch 3406.1 to 3406.N may be a transistor. Each outputswitch 3422.1 to 3422.N may also be a transistor.

Further, similar to the chemical detection circuit 3300, the outputsignal Vout of the chemical detection circuit 3400 may be converted intoa digital signal by an ADC. For example, the charging current I_(is) maybe digitized using a single-slope integration ADC or a dual-slopeintegrating ADC. In other embodiments, the output signal Vout of thechemical detection circuit 3400 may be converted into a digital signalby other known analog-to-digital (ND) conversion techniques.

Moreover, in one embodiment, the resistance of the resistor 3424 maydominate over the resistance of the series row-select switch (e.g.,3406.1 to 3406.N) to limit the current to be integrated onto thecapacitor C_(int) 3412.

FIG. 35 illustrates a block diagram of yet another chemical detectioncircuit 3500 according to yet another embodiment of the presentinvention. The chemical detection circuit 3500 may have a passtransistor 3524 that replaces the resistor 3424 of the chemicaldetection circuit 3400. Other than the transistor 3524, other parts ofthe chemical detection circuit 3500 may be identical to the chemicaldetection circuit 3400. The pass transistor 3524 may have a gate voltageV_(bias) tied to some process-, voltage-, and temperature (PVT)independent bias circuit. The on-resistance of this pass transistor 3524may be designed to dominate over the resistance of the series row-selectswitch in the pixel.

FIG. 36 illustrates a process 3600 for generating an output of achemical detection circuit according to an embodiment of the presentinvention. The process 3600 may be performed by the chemical detectioncircuits 3300, 3400 and 3500 as described above with respect to FIGS.33-35. The process 3600 may start at step 3602, at which a chemicaldetection pixel may be selected for readout. As shown in FIG. 33, forexample, when the chemical detection pixel 3302.1 is selected, therow-select switch 3306.1 may be closed. Alternatively, as shown in FIGS.34 and 35, for example, when the chemical detection pixel 3402.1 isselected, the row-select switch 3406.1 and the output switch 3422.1 maybe closed.

Then the process 3600 may proceed to step 3604. At step 3604, theprocess 3600 may integrate a readout current from the chemical detectionpixel to an integrator. As described above, the readout current may becaused by a voltage change at a gate terminal of the selected chemicaldetection pixel. In one embodiment, as shown in FIG. 33, the chemicaldetection pixel may work in a current mode, the selected chemicaldetection pixel may supply a readout current to charge a capacitor ofthe integrator. In another embodiment, as shown in FIGS. 34 and 35, thechemical detection pixel may work in a voltage mode and an outputvoltage from the chemical detection pixel may be converted by a resistoror a pass transistor to a current to charge the capacitor of theintegrator.

Then, at step 3506, the process 3600 may read out an output voltage ofthe integrator. As described above, output voltage of the integrator(Vout at the output of the amplifier 3310 or output of the amplifier3410) may have a better signal-to-noise ratio (SNR) for detection of ionconcentration of the analyte being analyzed by the chemical detectionpixel than instantaneous voltage measurement.

Although in the above description, the chemically-sensitive transistorsmay be described as PMOS devices, they may also be implemented as NMOSdevices in one embodiment. Further, the switches (e.g., row-selectedswitches, output switches, charge clear switches) may be implemented ineither PMOS or NMOS transistors in an embodiment.

Array Configuration and Readout Scheme

The described embodiments may provide a chemical detection circuit thatmay comprise a plurality of first output circuits at a first side and aplurality of second output circuits at a second and opposite side of thechemical detection circuit. The chemical detection circuit may furthercomprise a plurality of tiles of pixels each placed between respectivepairs of first and second output circuits. Each tile array may includefour quadrants of pixels. Each quadrant may have columns with designatedfirst columns interleaved with second columns. Each first column may beconnected to a respective first output circuit in first and secondquadrants, and to a respective second output circuit in third and fourthquadrants. Each second column may be connected to a respective secondoutput circuit in first and second quadrants, and to a respective firstoutput circuit in third and fourth quadrants.

Some embodiments may also provide a chemical detection system that maycomprise a motherboard having at least one central processing unit, anoutput device coupled to the mother board, and a chemical detectionreader board connected to the mother board. The chemical detectionreader board may have a chemical detection circuit that may comprise aplurality of first output circuits at a first side and a plurality ofsecond output circuits at a second and opposite side of the chemicaldetection circuit. The chemical detection circuit may further comprise aplurality of tiles of pixels each placed between respective pairs offirst and second output circuits. Each tile array may include fourquadrants of pixels. Each quadrant may have columns with designatedfirst columns interleaved with second columns. Each first column may beconnected to a respective first output circuit in first and secondquadrants, and to a respective second output circuit in third and fourthquadrants. Each second column may be connected to a respective secondoutput circuit in first and second quadrants, and to a respective firstoutput circuit in third and fourth quadrants.

Other embodiments may provide a method to read out data from a chemicaldetection circuit. The method may comprise selecting a first quadrant ofa tile to read out data, selecting one group of first columns and onegroup of second columns, reading out data of the group of first columnsfrom a first set of output pins located at a first side of the chemicaldetection circuit, reading out data of the group of second columns froma second set of output pins located at a second side of the chemicaldetection circuit, and repeating selection and data readouts for nextgroups of first columns and second columns till all remaining columns ofthe first quadrant are read out.

FIG. 37 illustrates a block diagram of a chemical detection circuit 3700according to an embodiment of the present invention. The chemicaldetection circuit 3700 may comprise a plurality of tiles of pixels3702.1-3702.N and 3704.1-3704.N, output circuits 3706 and 3708, controllogic and digital interface 3710, and bias circuit and diagnostic outputlogic 3712. Each tile 3702.1-3702.N and 3704.1-3704.N may include pixelsformed in columns with each column containing many rows. For example,each tile may contain 6848 columns×11136 rows of pixels. The tiles3702.1-3702.N may form a slice (e.g., a top slice) and the tiles3704.1-3704.N may form another slice (e.g., a bottom slice). Theplurality of tiles 3702.1-3702.N and 3704.1-3704.N may form aconglomerate pixel array. The output circuits 3706 and 3708 may beplaced at two opposite sides of the tiles (e.g., top and bottom). Theoutput circuits 3706 and 3708, control logic and digital interface 3710,and bias circuit and diagnostic output logic 3712 may each contain aplurality of pins for input and output data for the chemical detectioncircuit 3700. In one embodiment, the chemical detection circuit 3700 maybe formed on an integrated circuit chip. Further, in one embodiment, theoutput circuits 3706 and 3708 may include analog-to-digital converters(ADCs) to generate digital outputs. Moreover, in one embodiment, twoslices may be operated independently and exposed to a different analyte.For example, while data is being read out for the top tile, the bottomtile may be flushed out of fluid for another round of test. This may beused in conjunction with a dual-channel flow cell (e.g., mounted on topof the chemical detection circuit 3700) that two different flow channelsmay carry out different tasks at the same time.

Pixels of each tile 3702.1-3702.N and 3704.1-3704.N may be divided intofour quadrants and data generated at each pixel may be read out fromeither the top or the bottom. An exemplary configuration of the pixelswithin a pair of tiles is shown in FIG. 38A.

FIG. 38A illustrates a block diagram 3800 of components of the chemicaldetection circuit 3700 (of FIG. 37) according to an embodiment of thepresent invention. As shown in FIG. 38A, the tile 3702.1 may comprisefour quadrants: top left (TL) quadrant 3802, top right (TR) quadrant3804, bottom left (BL) quadrant 3806, bottom right (BR) quadrant 3808;and four row select registers: top left row select register 3828, topright row select register 3836, bottom left row select register 3830,bottom right row select register 3838. The tile 3704.1 may comprise fourquadrants: top left quadrant 3816, top right quadrant 3818, bottom leftquadrant 3812, bottom right quadrant 3814; and four row select registerseach for a respective quadrant: top left row select register 3832, topright row select register 3844, bottom left row select register 3834,bottom right row select register 3846. The tiles 3702.1 and 3704.1 mayshare a current sources and swizzles block 3810. The current sources andswizzles block 3810 may be sandwiched between the pair of tiles.Further, the tiles 3702.1 and 3704.1 may share top and bottom outputcircuits including channel circuits 3820 and 3822, column multiplexers3848 and 3850, output multiplexers 3824 and 3826, and output buffers3840 and 3842. The channel circuits 3820 and 3822 may include sample andhold (S/H) circuits. In one embodiment, each quadrant of the tile maycomprise a plurality of columns that each may include a plurality ofrows. For example, a quadrant may have 1712 columns that each maycontain 2784 rows of pixels. In one embodiment, each tile may includereference pixels. For example, a predetermined number (e.g., 4) ofcolumns and or rows of pixels at outer peripheral of each tile may bedesignated as reference pixels. The reference pixels may be used togenerate signals representing the background and are not exposed to theanalyte.

Each column may generate an output signal when one row of pixels isselected according to the respective row select register for thequadrant. In one embodiment, each column of a quadrant may be designatedas a first or second column (e.g., an odd column or even column), andthe output signal may be read from either the top or the bottom outputcircuits. The columns may be grouped for parallel read out operation.That is, a group of first columns or a group of second columns (ncolumns, n being an integer larger than one) may be read out togethersimultaneously in parallel. For example, if n is equal to 8, odd columngroups may be columns [1:8], [17:24], [33:40], etc., and even columngroups may be [9:16], [25:32], [41:48], etc. The column groups may beconnected according to quadrant they are in. For a top left quadrant(e.g., 3802, 3812) odd column groups may be connected to the outputcircuit at a first side (e.g., top output circuits including the channelcircuit 3820, column multiplexer 3848, output multiplexer 3824 andoutput buffer 3840) and even column groups may be connected to theoutput circuit at a second side (e.g., bottom output circuits includingthe channel circuit 3822, column multiplexer 3850, output multiplexer3826 and output buffer 3842). For a top right quadrant (e.g., 3804,3814) odd column groups may be connected to the output circuit at thefirst side and even column groups may be connected to the output circuitat the second side. For a bottom left quadrant (e.g., 3806, 3816) oddcolumn groups may be connected to the output circuit at the second sideand even column groups may be connected to output circuit at the firstside. For a bottom right quadrant (e.g., 3808, 3818) odd column groupsmay be connected to the output circuit at the second side and evencolumn groups may be connected to the output circuit at the first side.

In one embodiment, a group of first columns and a group of secondcolumns may form a data channel to be read out together simultaneouslyfrom either the first or the second side of the output circuits. Eachdata channel may comprise one group of first columns and one group ofsecond columns located in each quadrant between a first side of outputcircuits and a second side of output circuits (e.g., n first columns andn second columns from each of TL 3802, BL 3806, BL 3816, TL 3812).

The readout operation may use the row select shift registers (e.g., avertical shift register) to select rows and column shift registers toselect columns (e.g., a horizontal shift register). When the operationstarts, switches inside the current sources and swizzles block 3810 maybe enabled to provide driving currents to the signal lines, any pixelselect lines of an unused flow cell may be disabled, all row and columnshift registers may be reset. Then, the vertical shift register maystart counting by increments of 1 and the horizontal shift register maystart counting by 16. Data for the frame may start with the verticalshift registers selecting row 1 of TL, TR, BL, and BR since reset. Inone embodiment, the word “swizzle” may refer to the configuration that ametal line which passes through one column in the top circuitry may berouted in the space between the top and bottom circuitry in such a waythat it passes through a different column in the bottom circuitry, asshown below in FIG. 40.

The readout operation may start with a TL quadrant (e.g., the TLquadrant 3802). The first group of odd columns (e.g., n first columns[1:8]) in TL 3802 and first group of even columns (e.g., n secondcolumns [9:16]) in TL 3802 may be selected by the horizontal shiftregisters. Selected odd column pixels in row 1 of TL 3802 may be routedto top outputs through the channel circuit 3820, column multiplexer3848, output multiplexer 3824 and then they may be read out through thetop output buffer 3840. At the same time, the selected even columnpixels in row 1 of TL may be routed to bottom outputs through thechannel circuit 3822, column multiplexer 3850, output multiplexer 3826and then they may read out through the bottom output buffer 3842.

During the above readout time, the next group of odd pixels (e.g.,columns [17:24]) in row 1 of TL 3802 may be connected to the top columnmultiplexer 3848 and output multiplexer 3824 via the channel circuit3820. Similarly, the next group of even pixels (e.g., columns [25:32])in row 1 of TL 3802 may be connected to the bottom column multiplexer3850 and output multiplexer 3826 via the channel circuit 3822. Then, thetop and bottom output multiplexers 3824 and 3826 may switch theirrespective multiplexers, and subsequently, the next group of odd pixelsin row 1 of TL 3802 may be read out through the top outputs, and thenext group of even pixels in row 1 of TL 3802 may be read out throughthe bottom outputs. This may continue until all pixels from row 1 of TL3802 have been read out. At the end of the read out of row 1, the TL3802's vertical shift register may shift to the next row, and theoutputs may begin to settle.

After row 1 of the TL quadrant 3802 is finished, the readout operationmay continue to TR quadrant 3804. A first group of odd columns (e.g.,columns [1:8]) in TR quadrant 3804 and a first group of even columns(e.g., columns [9:16]) in TR quadrant 3804 may be selected by thehorizontal shift registers. Then the selected first group of odd columnpixels in row 1 of TR quadrant 3804 may be routed to top outputs throughthe channel circuit 3820, column multiplexer 3848, output multiplexer3824 and then they may be read out through the top output buffer 3840.At the same time, the selected first group of even column pixels [9:16]in row 1 of TR 3804 may be routed to bottom outputs through the channelcircuit 3822, column multiplexer 3850, output multiplexer 3826 and thenthey may read out through the bottom output buffer 3842.

During the above readout time, the next group of odd pixels (e.g.,columns [17:24]) in row 1 of TR 3804 may be connected to the top columnmultiplexer 3848 and output multiplexer 3824 via the channel circuit3820. Similarly, the next group of even pixels (e.g., columns [25:32])in row 1 of TR 3804 may be connected to the bottom column multiplexer3850 and output multiplexer 3826 via the channel circuit 3822. Then, thetop and bottom output multiplexers 3824 and 3826 may switch theirrespective multiplexers, and subsequently, the next group of odd pixelsin row 1 of TR 3804 may be read out through the top outputs, and thenext group of even pixels in row 1 of TR 3804 may be read out throughthe bottom outputs. This may continue until all pixels from row 1 of TR3804 have been read out. At the end of the read out of row 1, the TR3804's vertical shift register may shift to the next row, and theoutputs may begin to settle.

After row 1 of the TR quadrant 3804 is finished, the readout operationmay continue to BL quadrant 3806. A first group of odd columns (e.g.,columns [1:8]) in BL quadrant 3806 and a first group of even columns(e.g., columns [9:16]) in BL quadrant 3806 may be selected by thehorizontal shift registers. Then the selected first group of odd columnpixels in row 1 of BL quadrant 3806 may be routed to bottom outputsthrough the channel circuit 3822, column multiplexer 3850, outputmultiplexer 3826 and then they may read out through the bottom outputbuffer 3842. At the same time, the selected first group of even columnpixels [9:16] in row 1 of BL 3806 may be routed to top outputs throughthe channel circuit 3820, column multiplexer 3848, output multiplexer3824 and then they may be read out through the top output buffer 3840.

During the above readout time, the next group of odd pixels (e.g.,columns [17:24]) in row 1 of BL 3806 may be connected to the bottomcolumn multiplexer 3850 and output multiplexer 3826 via the channelcircuit 3822. Similarly, the next group of even pixels (e.g., columns[25:32]) in row 1 of BL 3806 may be connected to the top columnmultiplexer 3848 and output multiplexer 3824 via the channel circuit3820. Then, the top and bottom output multiplexers 3824 and 3826 mayswitch their respective multiplexers, and subsequently, the next groupof odd pixels in row 1 of BL 3806 may be read out through the bottomoutputs, and the next group of even pixels in row 1 of BL 3806 may beread out through the top outputs. This may continue until all pixelsfrom row 1 of BL 3806 have been read out. At the end of the read out ofrow 1, the BL 3806's vertical shift register may shift to the next row,and the outputs may begin to settle.

After row 1 of the BL quadrant 3806 is finished, the readout operationmay continue to BR quadrant 3808. A first group of odd columns (e.g.,columns [1:8]) in BR quadrant 3808 and a first group of even columns(e.g., columns [9:16]) in BR quadrant 3808 may be selected by thehorizontal shift registers. Then the selected first group of odd columnpixels in row 1 of BR quadrant 3808 may be routed to bottom outputsthrough the channel circuit 3822, column multiplexer 3850, outputmultiplexer 3826 and then they may read out through the bottom outputbuffer 3842. At the same time, the selected first group of even columnpixels [9:16] in row 1 of BR quadrant 3808 may be routed to top outputsthrough the channel circuit 3820, column multiplexer 3848, outputmultiplexer 3824 and then they may be read out through the top outputbuffer 3840.

During the above readout time, the next group of odd pixels (e.g.,columns [17:24]) in row 1 of BR quadrant 3808 may be connected to thebottom column multiplexer 3850 and output multiplexer 3826 via thechannel circuit 3822. Similarly, the next group of even pixels (e.g.,columns [25:32]) in row 1 of BR quadrant 3808 may be connected to thetop column multiplexer 3848 and output multiplexer 3824 via the channelcircuit 3820. Then, the top and bottom output multiplexers 3824 and 3826may switch their respective multiplexers, and subsequently, the nextgroup of odd pixels in row 1 of BR quadrant 3808 may be read out throughthe bottom outputs, and the next group of even pixels in row 1 of BRquadrant 3808 may be read out through the top outputs. This may continueuntil all pixels from row 1 of BR quadrant 3808 have been read out. Atthe end of the read out of row 1, the BR quadrant 3808's vertical shiftregister may shift to the next row, and the outputs may begin to settle.

After row 1 of all four quadrants are read out, the operation may returnto TL, and the pattern may be repeated until all rows in TL, TR, BL, andBR are read out to complete one frame for a tile (e.g., 3702.1). Andthen, the operation may be carried on in a next tile (e.g., 3702.2).This scheme may allow row n in a quadrant to settle for ¾ of the timethat it takes to read out row n from all four quadrants.

In one embodiment, the readout operation may be performed to completeone quadrant at a time. That is, after one row for a quadrant hasfinished, move on to the next row of the same quadrant; and continue toa next quadrant only after all rows of same the quadrant are finished.

In one embodiment, the tiles at the top slice (e.g., 3702.1˜3702.N) mayoperate concurrently, and the tiles at the bottom slice may operatealternately with corresponding tiles of the top slice (e.g., 3702.1 and3704.1 would operate alternately.).

FIG. 38B illustrates shift directions in different quadrants of a tileaccording to an embodiment of the present invention. As shown in FIG.38B, in one embodiment, the readout operation may start from the centerof a tile and move outward (e.g., increment the row and column selectregisters).

FIG. 39 illustrates a block diagram of part of a data channel 3900 ofthe chemical detection circuit 3700 according to an embodiment of thepresent invention. The data channel 3900 may comprise n first columns3902 and n second columns 3904 of TL quadrant 3802, and n first columns3908 and n second columns 3906 of BL quadrant 3806. FIG. 39 only showsthe data channel 3900 in the top slice (e.g., TL quadrant 3802 and BLquadrant 3806 of the tile 3702.1). Although not shown, the data channel3900 may further comprise n first columns and n second columns in eachof TL quadrant 3812 and BL quadrant 3816 of the tile 3704.1. As shown inFIG. 39, the data channel 3900 may have two 2n signal lines with top 2nsignal lines connected to the output channel circuit 3820 at the rightside. Although not shown, the bottom 2n signal lines may be connected tothe output channel circuit 3822 to the left side. The pixels of the nfirst columns 3902 and the n second columns 3906 may each be connectedto a respective top 2n signal lines. The pixels of the n second columns3904 and the n first columns 3908 may each be connected to a respectivebottom 2n signal lines. The current sources and swizzles block 3810 atthe left side of the 2n signal lines may provide 2n current sources thateach may drive a respective signal line. Further, the 2n signal linesmay be swizzled in the current sources and swizzles block 3810 (detailsof one exemplary embodiment of the swizzle will be described later withrespect to FIG. 40).

During operation, data from the top 2n signal lines may be read out fromthe channel circuit 3820, column multiplexer 3848, output multiplexer3824 and output buffer 3840 and the bottom 2n signal lines may bereadout from corresponding circuits at the left.

FIG. 40 illustrates a swizzle configuration of signal lines of thechemical detection circuit 3700 (of FIG. 37) according to an embodimentof the present invention. In one embodiment of the chemical detectioncircuit 3700, there may be two output lines running through each columnso that a column of pixels may be connected to the column circuitry atthe top of the chemical detection circuit 3700 (e.g., the IC chip) or tothe column circuitry at the bottom of the chemical detection circuit3700. The column output lines may run the full height of the die and maybe very long, and therefore may be susceptible to crosstalk. To reducecrosstalk, the column output lines may be swizzled in the middle of thechemical detection circuit 3700 (e.g., in the current sources andswizzles block 3810 of FIG. 38A). As shown in FIG. 40, the four columnsmay have 8 wires (e.g., each column may contain two wires). Each wiremay be connected to either the top column circuitry 4002 or the bottomcolumn circuitry 4004. For example, the wires A, D, E and H may beconnected to the top column circuitry 4002 and wires B, C, F and G maybe connected to the bottom column circuitry 4004. The sequence of the 8wires may be swizzled in the middle. For example, top half of wire A mayrun through pixels of column 1 and bottom half of wire A may run throughpixels of column 2, top half of wire B may run through pixels of column1 and bottom half of wire B may run through pixels of column 3, top halfof wire C may run through pixels of column 2 and bottom half of wire Cmay run through pixels of column 1, top half of wire D may run throughpixels of column 2 and bottom half of wire D may run through pixels ofcolumn 4, top half of wire E may run through pixels of column 3 andbottom half of wire E may run through pixels of column 1, top half ofwire F may run through pixels of column 3 and bottom half of wire F mayrun through pixels of column 4, top half of wire G may run throughpixels of column 4 and bottom half of wire G may run through pixels ofcolumn 2, top half of wire H may run through pixels of column 4 andbottom half of wire H may run through pixels of column 3. In oneembodiment, the swizzle according to pattern shown in FIG. 40 may berepeated for every four columns. As a result, the crosstalk may bereduced by as much as 50%.

FIG. 41 illustrates a process 4100 for outputting data from a chemicaldetection circuit according to an embodiment of the present invention.The process 4100 may be performed by the chemical detection circuit3700. The process 4100 may start at step 4102, at which a first quadrantof a tile may be selected to read out data. As described above withrespect to FIG. 38A, for example, a readout operation may be performedfor a tile (e.g., 3702.1) by starting at the top left quadrant 3802.Then the process 4100 may proceed to step 4104. At step 4104, theprocess 4100 may select one group of first columns and one group ofsecond columns. As described above, the readout operation may beperformed in groups of first columns and second columns (e.g., oddcolumns [1:8] and even columns [9:16]). Then, at step 4106, the process4100 may read out data for the group of first columns from a first setof output pins (e.g., top output buffers 3840) and for the group ofsecond columns from a second set of output pins (e.g., bottom outputbuffers 3842).

Then the process 4100 may proceed to step 4108. At step 4108, theprocess 4100 may repeat selection and data readouts for a next group offirst columns and a next group of second columns until all remainingcolumns of the first quadrant are read out. For example, the chemicaldetection circuit 3700 may repeat the readout operation for odd columngroups [17:24], [33:40], etc. and even column groups [25:32], [41:48],etc. for all remaining columns of the first quadrant (e.g., TL quadrant3802).

FIG. 42 illustrates a system architecture 4200 for chemical detectionaccording to an embodiment of the present invention. The systemarchitecture 4200 may comprise a motherboard 4202, an output device4208, a reader board 4210 and a valve board 4212. The motherboard 4202may include CPUs 4204 and storage 4206 (e.g., a Double Date Rate (DDR)memory device). The CPUs 4204 may scale from 2 cores to 6 cores. Thememory DDRs 4206 may be 1 GB to 96 GB DDR3 (double data rate type 3).The motherboard 4202 may also support on board RAID (6 SATA ports) andgraphics processor board (GPU). The output device 4208 may be a colordisplay with high brightness (e.g., an XGA multi-touch input independentand display independent 8 wire analog resistive). The reader board 4210may include a sensor 4218 (e.g., the chemical detection circuit 3700)and other peripheral circuits (details shown in FIGS. 43 and 44 foranalog and digital chemical sensors respectively). The valve board 4212may include a FPGA 4214 and valve controls 4216. During operation, theFPGA 4214 may be loaded with control logic to control the operation ofthe valve board. The valve controls 4216 may include a plurality ofvalves (e.g., 30 valves) that controls flow of fluid containing analyteto be analyzed by the sensor 4218. The valve board 4212 may furtherinclude thermistor inputs, pressure sensor inputs and may furtherinclude heater/cooler controls (not shown) that may controlheaters/coolers for the sensor 4218 and analytes (e.g., to assist incontrolling reactions during the testing of samples). In one embodiment,the motherboard 4202 and the reader board 4210 may be connectedaccording to the PCI express (PCIe) standard, the reader board 4210 andthe valve board 4212 may be connected by serial link over LVDS(low-voltage differential signaling).

FIG. 43 illustrates an analog reader board 4300 for a chemical detectioncircuit according to an embodiment of the present invention. The analogreader board 4300 may include an analog chemical sensor 4302, a clock4304, a power supply 4306, a serial link for LVDS 4308, a reader FPGA4310, a memory 4312, ADCs 4314, a PCIe switch 4316, a PCIe connector4318, two satellite FPGA blocks 4320 and 4322, and a voltage referenceand DACs block 4324. The analog chemical sensor 4302 may be an IC chipembodiment of chemical detection circuit 3700. The analog data read outfrom the analog chemical sensor 4302 may be digitized by the ADCs 4314,which may use voltage references and DACs 4324. The digitized data maybe sent to the satellite FPGAs 4320 or 4322, which may perform settlingcorrection, and then sent to the reader FPGA 4310. The reader FPGA 4310may buffer data in the memory 4312, which may include a plurality of DDRmemory blocks. The reader FPGA 4310 may also perform frame averaging(e.g., average a pixel's data value among multiple frames; this ispossible because the analog chemical sensor may read out data at a framerate higher than required (e.g., 30 FPS) or variable rate frameaveraging (e.g., average different portions of a pixels time history ata different rate) and then send data out to a server motherboard (e.g.,motherboard 4202 of FIG. 42) via PCIe switch 4316 and PCIe connector4318. The PCIe switch 4316 may include multiplexers that multiplex linksto a PCIex 16 link of the PCIe connector 4318. The LVDS 4308 may provideserial links to a valve board (e.g., the valve board 4212 of FIG. 42).The power of the reader board 4300 may be provided by the power supply4306 and the timing signals may be provided by the clock 4304. In oneembodiment, the ADCs 4314 may be placed close to the analog chemicalsensor 4302.

FIG. 44 illustrates a digital reader board 4400 for a chemical detectioncircuit according to an embodiment of the present invention. The digitalreader board 4400 may include a digital chemical sensor 4402, a clock4404, a power supply 4406, a serial link for LVDS 4408, a reader FPGA4410, a memory 4412, a PCIe switch 4416, and a PCIe connector 4418. Thedigital chemical sensor 4402 may be an IC chip embodiment of chemicaldetection circuit 3700 (of FIG. 37) with ADCs incorporated on the chipthat digitize the output data signals on-chip. The clock 4404, powersupply 4406, serial link for LVDS 4408, reader FPGA 4410, memory 4412,PCIe switch 4416, and PCIe connector 4418 may perform functions similarto their counterparts on the analog digital reader board 4300. In oneembodiment, the digital chemical sensor 4402 may be placed on areplaceable board separate from the digital reader board 4400.

FIG. 45 illustrates a block diagram 4500 of an output configuration fora chemical detection circuit according to an embodiment of the presentinvention. The block diagram 4500 may show an analog front end and noisecalculations for analog data output from an analog chemical detector4502. The DAC 4504 may generate analog signals according to digitalreference values, and analog signals from the DAC 4504 may be bufferedby the buffers 4506.1˜4506.4. The output from analog chemical detector4502 may be amplified by the amplifiers 4508.1˜4508.4 and the amplifiedsignals may be filtered by the low pass filters 4510.1˜4510.4. Thefiltered signals may be input to the ADC module 4512, which may containa plurality of differential amplifiers 4514.1˜4514.4. The amplifiedsignals may pass another round of low pass filters 4516.1˜4516.4 andthen finally the signals may be converted by the Quad ADC 4518 intodigital data and sent to FPGAs. The Quad ADC 4518 may receive clocksignals from a clock fanout 4524. The clock signals may be generated bya PLL 4522 based on signals from an oscillator 4520. In one embodiment,the analog chemical detector 4502 may be an IC chip embodiment of thechemical detection circuit 3700.

FIG. 46 illustrates a block diagram 4600 of bandwidth utilization for achemical detection circuit according to an embodiment of the presentinvention. An analog chemical detector 4602 may send its data to aplurality of ADCs 4604. The ADCs 4604 may send digital data to theFPGA(s) 4606, which may in turn send data to CPU(s) 4608 and storageunits 4616 and 4618 (e.g., DDR3 memory). The CPU(s) 4608 may cache datain a memory cache 4610 (e.g., DDR3 memory) and hard drives 4612 and4614. In one embodiment, the analog chemical detector 4602 may be an ICchip embodiment of the chemical detection circuit 3700. The numbersgiven in FIG. 46 may be theoretical maximums. The FPGA(s) 4606 mayperform a 3:1 compression of samples (e.g., settling correction) and a2:1 or greater compression of frames (e.g. frame averaging).

FIG. 47 illustrates a block diagram 4700 for clock distribution for ananalog reader board (e.g., the analog reader board 4300 of FIG. 43)according to an embodiment of the present invention. The clock signalsfor various components of an analog reader board may be generated basedon a 100 MHz oscillator 4702. The clock generator 4704 may receive thesignals from the 100 MHz oscillator 4702 and generate various clocksignals. For example, the clock generator 4704 may generate 120 MHzclock signals to be sent to two zero delay buffers 4706.1 and 4706.2, aflip flop 4716 and a first PLL of the FPGA 4714 (e.g., the reader FPGA4310 of the analog reader board 4300). The zero delay buffers 4706.1 and4706.2 may provide the 120 MHz clock signals to ADC sets 4718.1 and4718.2 for the ADCs to send digitized data to FPGAs 4720.1 and 4720.2(e.g., the satellite FPGAs 4320 and 4322 of the analog reader board4300) at a frequency of, for example, 840 MHz. The first PLL of the FPGA4714 may send clock signals to first PLLs in respective FPGAs 4720.1 and4720.2, and may also send a clock signal internally to a flip flop portof the FPGA 4714. The flip flop 4716 may generate channelincrement/decrement signals for data read out based on an output of theflip flop port of the FPGA 4714 and the 120 MHz clock signal from theclock generator 4704. The oscillator 4702 may also generate a 33 MHzclock signal for a clock driver 4708, which may provide clock signalsfor second PLLs in the FPGAs 4720.1 and 4720.2 respectively and for asecond PLL in the FPGA 4714. The second PLL in the FPGA 4714 maygenerate an internal clock (e.g., 267 MHz). In one embodiment, basingall of these clocks may allow for the synchronization of the channeloutputs of the sensor and the sampling by the ADCs.

Communication external to the analog board reader may be based on a 100MHz clock signals from a PCIe connector. The 100 MHz clock signals fromPCIe connector may be buffered by a PCIe clock buffer 4710. The buffered100 MHz clock signals may be sent to first and second SerDes PLL(serialization/deserialization phase locked loop) of the FPGA 4714 andmay also be sent to a PCIe switch 4712 (e.g., PCIe switch 4316).

In one embodiment, the zero delay buffers 4706.1 and 4706.2 may allowfor skew adjustment between ADC sample clocks and data channels of achemical detector (not shown). The clocks may be differential LVDS wherepossible, but the clocks for channels of the chemical detector may bedifferential low-voltage positive emitter-coupled logic (LVPECL).Further, in one embodiment, the combination of ADC and data channel 120MHz clocks need to be low jitter (e.g., <15 ps—as drawn ˜4.5 rms). Inone embodiment, in the case of the analog chemical sensor, the “clock”provided to the sensor may be the “channel increment/decrementsignal”—allowing for synchronization of channel switch and sampling bythe ADCs.

FIG. 48 illustrates a block diagram 4800 for power distribution ofsystem components according to an embodiment of the present invention. APC power supply 4802 may be coupled to an AC input. The valve board 4804(e.g., the valve board 4212 of the system architecture 4200) may receivepower from the PC power supply 4802 by two 4-pin connectors. Themotherboard 4806 (e.g., the motherboard 4202 of the system architecture4200) may receive power from the PC power supply 4802 by two 8-pinconnectors and a 24-pin connector. The 24-pin cable to provide power tothe motherboard 4806 may be “Y-cabled” to also provide power to thereader board 4808 (e.g., the reader board 4210 of system architecture4200, which may be an analog reader board (e.g., 4300) or digital readerboard (e.g., 4400)). The reader board 4808 may include an onboard powersupply 4810 that may include a plurality of power regulators (e.g., lowdropout linear regulator, programmable output low dropout regular)and/or DC/DC power supplies (e.g., high voltage high current DC/DC powersupply). In one embodiment, all of the DC/DC switching power suppliesmay be synchronized with the main reader board clock. This may keep anyswitching noise from the power supplies from “beating” against theclocks used elsewhere. Further, the clocks for the switching powersupplies may be arranged in time such that the instantaneous currentload on the PC power supply is minimized.

FIG. 49 illustrates a block diagram 4900 for DACs of an analog readerboard according to an embodiment of the present invention. The DACconfiguration 4900 may include a voltage reference 4902, a DAC 4904, alow pass filter including a resistor 4906 and a capacitor 4908. Thefiltered signal may be amplified by an operational amplifier 4910. Theoutput from the operational amplifier 4910 may be filtered by a bead4912 and a plurality of capacitors 4914 (e.g., a bulk LPF/LF charge).The filtered signal then may be sent to first inputs of the operationalamplifiers 4916.1˜4916.4 via local decoupling circuits (e.g., thecapacitors 4918 and corresponding resistors 4920). The second inputs tothe operational amplifiers 4916.1˜4916.4 may be respective channelinputs 4924.1˜4924.4. The output of the operational amplifiers4916.1˜4916.4 may be coupled back to the first inputs via respectivefeedback resistors 4922.1˜4922.4. In one embodiment, a plurality of DACsmay be provided for channel offset, references voltages, electrodedrive, built-in self-test (BIST) drive and ISFET Bias.

FIG. 50 illustrates a block diagram of FPGA configuration for an analogreader board 5000 according to an embodiment of the present invention.The analog reader board 5000 may be an embodiment of the analog readerboard 4300. The analog reader board 5000 may comprise a plurality of ADCmodules 5002.1 and 5002.2, two satellite FPGAs 5004.1 and 5004.2 (e.g.,satellite FPGAs 4320 and 4322), a reader FPGA 5006 (e.g., reader FPGA4310) and its memory modules 5008.1 and 5008.2, a PCIe switch 5010(e.g., PCIe switch 4316), an analog chemical sensor 5012 (e.g., analogchemical sensor 4302), LVDS drivers and receivers 5014 (e.g., LVDS 4308)and a plurality of DAC modules 5016 and 5018. In one embodiment, eachADC of the ADC modules 5002.1 and 5002.2 may include a PLL. Thesatellite FPGAs 5004.1 and 5004.2 may perform sample averaging, whichmay be controlled by Dstrobe signal from the reader FPGA 5006 andsoftware setup in the satellite FPGAs 5004.1 and 5004.2. Moreover, inone embodiment, the control logic for the reader FPGA 5006 may be loadedfrom the memory modules 5008.1 and/or 5008.2, which may be SPI flashdevices (e.g., EEPROM) that hold two images: (1) a default “loader”image, and (2) a current run-time image. The control logic (e.g.,images) for the satellite FPGAs 5004.1 and 5004.2 may be loaded by thereader FPGA 5006 from a motherboard (e.g., motherboard 4202) over PCIe.Further, in one embodiment, the FPGAs (including the valve FPGA 4214)may be de-configured and reloaded by a PCIe reset. Also, PCIenumerations may be trigged once PCIe FPGA may be programmed.

FIG. 51 illustrates a block diagram of FPGA power monitoring for areader board 5100 according to an embodiment of the present invention.The reader board 5100 may be an embodiment of the reader board 4808. Thereader board 5100 may comprise a power supply module 5102 (e.g., powersupply 4810) that receives 5V and 12 V inputs from a 24 pin connector5106. The power supply module 5102 may provide power to the rest ofreader 5104. The output voltages from the power supply module 5102 maybe monitored by a plurality of voltage monitors 5108 and 5112. The firstvoltage monitor 5108 may receive its power supply VCC from the 24 pinconnector 5106 and generate a reset RST signal if one of the monitoredvoltage (including VCC) deviates more than a threshold from apredetermined voltage level (e.g., 1.5% deviation). The RST signal fromthe voltage monitor 5108 may be “OR”-ed with a reset signal from a PCIeconnector 5110 by an OR gate 5116. The output of the OR gate 5116 may beinput as a monitored voltage for the second voltage monitor 5112, whichmay also receive its power supply VCC from the 24 pin connector 5106 andgenerate a reset RST signal if one of the monitored voltage (includingVCC) deviates more than a threshold from a predetermined voltage level(e.g., 1.5% deviation). The RST signal from the voltage monitor 5112 maybe sent to a clock driver 5114, which may generate a reset signal andnCONFIG signal to the rest of reader 5104. The reset signal from theclock driver 5114 may be sent to a PCIe switch of the reader board. ThenCONFIG signal from the clock driver 5114 may be sent to a FPGA of thereader board to cause the FPGA to reload. In one embodiment, “OR”-ingthe RST signal from the voltage monitor 5108 with the reset signal fromthe PCIe connector 5110 may guarantee the nCONFIG pulse widthrequirements being met.

Column ADC and Serializer Circuit

The described embodiments may provide a chemical detection circuit thatmay comprise a column of chemically-sensitive pixels. Eachchemically-sensitive pixel may comprise a chemically-sensitivetransistor and a row selection device. The chemical detection circuitmay further comprise a column interface circuit coupled to the column ofchemically-sensitive pixels and an analog-to-digital converter (ADC)coupled to the column interface circuit.

Some embodiments may also provide a chemical sensor that may comprise aplurality of columns of chemically-sensitive pixels. Each column maycomprise a plurality of chemically-sensitive pixels formed in rows. Eachchemically-sensitive pixel may comprise a chemically-sensitivetransistor and a row selection device. The chemical sensor may furthercomprise a column interface circuit coupled to the column ofchemically-sensitive pixels and an analog-to-digital converter (ADC)coupled to the column interface circuit.

Other embodiments may provide a method of generating an output signalfor a chemical detection circuit. The method may comprise generating arow selection signal by a row decoder of the chemical detection circuit.The chemical detection circuit may have a pixel array that includes acolumn of chemical detection pixels. Each chemical detection pixel mayinclude a chemically-sensitive transistor and a row selection device.The method may further comprise applying the row selection signal to arespective row selection device of a selected chemical detection pixel,converting an analog signal at a readout signal line of the column ofchemical detection pixels to a digital signal by an Analog-to-Digitalconverter (ADC) and outputting the converted digital signal as theoutput signal for the chemical detection circuit.

The described embodiments may further provide a chemical detectioncircuit that may comprise a pixel array comprising a plurality ofchemically-sensitive pixels formed in columns and rows. Eachchemically-sensitive pixel may comprise a chemically-sensitivetransistor and a row selection device. The chemical detection circuitmay further comprise a pair of analog-to-digital converter (ADC) circuitblocks, a pair of input/output (I/O) circuit blocks coupled to the pairof ADC circuit blocks respectively and a plurality of serial linkterminals coupled to the pair of IO circuit blocks.

The described embodiments may further provide a method to read out datafrom a chemical detection device. The method may comprise reading datafrom a plurality of columns of chemically-sensitive pixels on thechemical detection device in parallel. Each chemically-sensitive pixelmay comprise a chemically-sensitive transistor and a row selectiondevice. The method may further comprise digitizing data read from theplurality of columns of chemically-sensitive pixels in parallel,serializing the digitized data in parallel for each column ofchemically-sensitive pixels respectively, and transmitting the buffereddigitized data on a plurality of serial links in parallel.

FIG. 52 illustrates a digital chemical detection circuit 5200 accordingto an embodiment of the present invention. The digital chemicaldetection circuit 5200 may be an IC chip comprising a pixel array 5202,row decoders 5204.1 and 5204.2, column ADCs 5206.1 and 5206.2, I/Ocircuits 5208.1, a plurality of bias circuits 5210.1˜5210.3, a timingsequencer 5212 and 5208.2 and a plurality of output terminalsD[0]˜D[N−1]. The pixel array 5202 may comprise chemical detection pixelsformed in columns with each column including a plurality of rows ofpixels. In one embodiment, the pixel array 5202 may include many tilesof pixels and the tiles may be placed in slices as described above withrespect to FIG. 37. The row decoders 5204.1 and 5204.2 may generate rowselection signals for rows of pixels based on control logic.

In one embodiment, the column ADCs 5206.1 and 5206.2 may include aplurality of ADCs each corresponding to one column. In anotherembodiment, the column ADCs 5206.1 and 5206.2 may include a plurality ofADCs and each ADC may be shared between several columns (e.g., using oneor more multiplexers). Moreover, in one embodiment, the column ADCs5206.1 and 5206.2 may perform offset cancellation.

The bias circuits 5210.1˜5210.3 may generate all bias and referencevoltages needed for the chemical detection circuit 5200 on chip. Thatis, the chemical detection circuit 5200 does not have any externalanalog references. The bias circuits 5210.1˜5210.3 may need an externalpower supply, such as VDDA to function. The timing sequencer 5212 mayprovide the internal timing signals for the chemical detection circuit5200.

The plurality of output terminals D[0]˜D[N−1] may provide serial linksto one or more devices external of the IC chip. The serial links may useprinted circuit board transmission lines. The signaling over thetransmission lines may use differential signaling or CMOS signaling. Thedifferential signaling may be any differential signaling scheme, forexample, Low-voltage differential signaling (LVDS) or current mode logic(CML). In one embodiment, half of the output pins may be placed on oneside of the chip 5200 and another half on an opposite side. The number Nmay be an even number (e.g., 24, 32). Further, in one embodiment, theserial interface may be programmable. For example, the strength of thedrivers may be programmed and tuned for a given system. The driver type(LVDS, CML, CMOS) may also be programmed. Moreover, on-chip terminationmay be enabled or disabled. Various aspects of the protocol may beconfigured such as run-length control and format.

FIG. 53 illustrates a more detailed block diagram 5300 of the outputcircuits of the digital chemical detection circuit of FIG. 52 accordingto an embodiment of the present invention. As shown in FIG. 53, columninterface 5302 may be connected to the pixel array (e.g., pixel array5202) to read data out of the pixel array. The column comparators 5304may include a plurality of comparators (e.g., ADCs). In one embodiment,the column comparators 5304 may perform offset cancellation.

The DACs 5312.1 and 5312.2 may provide reference voltages for the columncomparators 5304 to perform analog-to-digital conversion. A pair oflatches blocks 5306 and 5308 may provide buffer for the output data. Thedigitized data may be sent from the column comparators first to the Alatches 5306 and then sent from the A latches 5306 to the B latches 5308according to the control provided by the gray code blocks 5314.1 and5314.2. A plurality of output serializer 5310.1˜5310.n may be coupledbetween the buffer and the output terminals D[0]˜D[n−1] (e.g., n=N/2).The gray code circuits 5314.1˜5314.2 may distribute a digital count toall of the latches that are controlled by the comparators 5304 such thatwhen a given comparator transitions, the gray code may be latched intomemory. This gray code may be set to count synchronously with a DAC rampcircuit which establishes a global reference for all comparators of thecomparators 5304. When the global reference falls below the pixel valueheld at given column, a corresponding comparator may fire. Since thecomparator can transition asynchronous to the clock, the count may bedistributed with a gray code where only one bit transition is made atany time is used to avoid invalid codes.

In one embodiment, each output terminal may comprise two pins fordifferential signaling (e.g., low-voltage differential signaling). Inone embodiment, the A latches 5306 may be the master latches while the Blatches 5308 may be the slave latches. The latches may allow theanalog-to-digital conversion to run in parallel to the readout of apreviously converted row.

The on-chip bias and reference voltages may be provided by the bias andreference circuit block 5316. As shown in FIG. 53, the bias andreference circuit block 5316 may provide bias and reference voltages tothe column interface circuit 5302, the DACs 5312.1 and 5312.2, and graycode circuits 5314.1˜5314.2. Further, as shown in FIG. 53, the timingsequencer circuit 5320 may provide timing signals to the gray codecircuits 5314.1˜5314.2, DACs 5312.1˜5312.2, row decoders 5318.1˜5318.2,pixel controls and column controls. The timing sequencer 5320 may beconnected to pins TMODE, TEN, RST for reset and test modes. The timingsequencer 5320 may also be connected to pins for SDA, SCL, CLK forprogramming registers with a serial protocol such as SPI. The timingsequencer 5320 may control all the timing on the chip by advancing eachrow during a frame time and providing stimulus to the circuits duringeach row time. Because the pixel can operate in many different ways, thetiming sequencer 5320 may be reprogrammed to change the operation of thecontrol signals.

FIG. 54 illustrates a serializer circuit 5400 according to an embodimentof the present invention. The serializer circuit 5400 may comprise aplurality of shift registers 5402, bit alignment logic 5406, a pair ofping-pong registers 5406, a multiplexer 5408 to select one of theping-pong registers, a multiplexer 5410 to multiplex the output from themultiplexer 5408 and built-in self test (BIST), an encoder 5412, aserializer 5416 and driver 5418.

The shift registers 5402 may be part of the I/O buffer. In oneembodiment, as shown in FIG. 54, 14-bit shift registers may be used. Thedata shifted out of the shift registers may be sent to the bit alignmentlogic 5406, where the data may be aligned. For example, the 14-bits datamay be aligned to 8-bits data according to align control. The aligneddata from the alignment logic 5406 may be sent to the pair of ping-pongregisters 5406 that latch each parallel word with timing overlap toprevent glitches in the data.

Then, the multiplexer 5408 may select one of the pair of ping-pongregisters 5406 to output its data to the multiplexer 5410. Themultiplexer 5410 may select either the output data from the multiplexer5408 or the BIST data to be sent to the encoder 5412. To achieve DCbalance, an encoding scheme such as 8b/10b may be used. Thus, in oneembodiment, the encoder 5412 may be an 8B10B encoder. It should be notedthat other encoding schemes may also be applied. The encoded data fromthe encoder 5412 may be serialized in the serializer 5413 and sent outby the driver 5418. In one embodiment, the serializer 5413 may be drivenby a PLL clock signal. In one embodiment, the driver 5418 may beconfigured to transmit data signals by low-voltage differentialsignaling. In one embodiment, the driver 5418 may work in a differentialmode, in which one bit may be transmitted at each transmit clock signaland the pair of output pins may carry the differential data pair. Inanother embodiment, the driver 5418 may work in a dual-channel mode, inwhich two bits may be transmitted per transmit clock cycle in parallelby the pair of output pins of an output terminal.

FIG. 55 illustrates a more detailed block diagram 5500 As shown in FIG.55, the serializer 5413 may comprise a plurality of registers 5502, apair of multiplexers 5504, a pair of registers 5506, a multiplexer 5508and a buffer register 5510. The registers 5502 may each hold one bit ofthe encoded data. The registers 5502 may work at a clock speed at onetenth of the PLL clock signal. The output from the registers 5502 may besent to the pair of multiplexers 5504. Each of the multiplexers 5504 maygenerate an output to be sent to one of the pair of registers 5506. Thepair of registers 5506 may operate at one half of the clock speed of thePLL clock signal. The output from the pair of registers 5506 may beinput to the multiplexer 5508, which may select one of the outputs fromthe pair of registers 5506 to be the output. The output from themultiplexer 5508 may be sent to the buffer register 5510. The bufferregister 5510 may operate at the clock speed of the PLL clock signal tosend out its content to the driver 5418.

FIG. 56 illustrates a block diagram of a digital chemical detectioncircuit according to an embodiment of the present invention. FIG. 56shows a layout of a digital chemical detection circuit according to anembodiment of the present invention.

FIG. 57 illustrates a block diagram of another digital chemicaldetection circuit according to an embodiment of the present invention.FIG. 56 shows another layout of a digital chemical detection circuitaccording to an embodiment of the present invention.

FIG. 58 illustrates a block diagram of another digital chemicaldetection circuit 5800 according to an embodiment of the presentinvention. The digital chemical detection circuit 5800 may comprise apixel array 5802, a plurality of output circuits 5804.1˜5804.2, aplurality of serial output circuits 5806.1˜5806.2, a plurality of rowselect circuits 5808.1˜5808.2, a clock tree 5810 and a plurality ofthermometers 5812. The pixel array 5802 may be a 2T pixel array 1400shown in FIG. 14A and comprise a plurality of 2T pixels configuredaccording to FIG. 14A. The row select 5808.1˜5808.2 may be the rowdecoders as described above with respect to FIGS. 52-53. Also, theoutput circuits 5804.1˜5804.2 may include column interface, offsetcancellation and column ADC as described above with respect to FIGS.52-53. The serial output circuits 5806.1˜5806.2 may include theserializer circuits described above with respect to FIGS. 52-55. Theclock tree 5810 may be an embodiment of the timing sequencer describedabove with respect to FIGS. 52-53. In one embodiment, the digitalchemical detection circuit 5800 may include four thermometers placed onchip. Further, in one embodiment, the four thermometers may be placed ator near the four corners of the pixel array 5802.

Several embodiments of the present invention are specificallyillustrated and described herein. However, it will be appreciated thatmodifications and variations of the present invention are covered by theabove teachings. In other instances, well-known operations, componentsand circuits have not been described in detail so as not to obscure theembodiments. It can be appreciated that the specific structural andfunctional details disclosed herein may be representative and do notnecessarily limit the scope of the embodiments. For example, someembodiments are described with an NMOS. A skilled artisan wouldappreciate that a PMOS may be used as well.

Those skilled in the art may appreciate from the foregoing descriptionthat the present invention may be implemented in a variety of forms, andthat the various embodiments may be implemented alone or in combination.Therefore, while the embodiments of the present invention have beendescribed in connection with particular examples thereof, the true scopeof the embodiments and/or methods of the present invention should not beso limited since other modifications will become apparent to the skilledpractitioner upon a study of the drawings, specification, and followingclaims.

Various embodiments may be implemented using hardware elements, softwareelements, or a combination of both. Examples of hardware elements mayinclude processors, microprocessors, circuits, circuit elements (e.g.,transistors, resistors, capacitors, inductors, and so forth), integratedcircuits, application specific integrated circuits (ASIC), programmablelogic devices (PLD), digital signal processors (DSP), field programmablegate array (FPGA), logic gates, registers, semiconductor device, chips,microchips, chip sets, and so forth. Examples of software may includesoftware components, programs, applications, computer programs,application programs, system programs, machine programs, operatingsystem software, middleware, firmware, software modules, routines,subroutines, functions, methods, procedures, software interfaces,application program interfaces (API), instruction sets, computing code,computer code, code segments, computer code segments, words, values,symbols, or any combination thereof. Determining whether an embodimentis implemented using hardware elements and/or software elements may varyin accordance with any number of factors, such as desired computationalrate, power levels, heat tolerances, processing cycle budget, input datarates, output data rates, memory resources, data bus speeds and otherdesign or performance constraints.

Some embodiments may be implemented, for example, using acomputer-readable medium or article which may store an instruction or aset of instructions that, if executed by a machine, may cause themachine to perform a method and/or operations in accordance with theembodiments. Such a machine may include, for example, any suitableprocessing platform, computing platform, computing device, processingdevice, computing system, processing system, computer, processor, or thelike, and may be implemented using any suitable combination of hardwareand/or software. The computer-readable medium or article may include,for example, any suitable type of memory unit, memory device, memoryarticle, memory medium, storage device, storage article, storage mediumand/or storage unit, for example, memory, removable or non-removablemedia, erasable or non-erasable media, writeable or re-writeable media,digital or analog media, hard disk, floppy disk, Compact Disc Read OnlyMemory (CD-ROM), Compact Disc Recordable (CD-R), Compact DiscRewriteable (CD-RW), optical disk, magnetic media, magneto-opticalmedia, removable memory cards or disks, various types of DigitalVersatile Disc (DVD), a tape, a cassette, or the like. The instructionsmay include any suitable type of code, such as source code, compiledcode, interpreted code, executable code, static code, dynamic code,encrypted code, and the like, implemented using any suitable high-level,low-level, object-oriented, visual, compiled and/or interpretedprogramming language.

What is claimed is:
 1. A chemical detection circuit, comprising: aplurality of first output circuits at a first side of the chemicaldetection circuit; a plurality of second output circuits at a secondside of the chemical detection circuit, the second side being oppositeto the first side; and a plurality of tiles of pixels each placedbetween a respective first output circuit and a respective second outputcircuit, each tile comprising: four quadrants of pixels, each quadrantcomprising: a plurality of first columns; and a plurality of secondcolumns interleaved with the plurality of first columns, each firstcolumn and second column having a plurality of pixels formed in rows,wherein each first column in first and second quadrants is coupled tothe respective first output circuit, and each second column in first andsecond quadrants is coupled to the respective second output circuit,wherein each first column in third and fourth quadrants is coupled tothe respective second output circuit, and each second column in thirdand fourth quadrants is coupled to the respective first output circuit.2. The chemical detection circuit of claim 1, wherein each pixelincludes an ion-sensitive field effect transistor (ISFET).
 3. Thechemical detection circuit of claim 1, wherein the plurality of tilesare lined up in two slices in parallel, each tile from a first slice anda corresponding tile from a second slice form a respective pair oftiles, each pair of tiles are placed between a respective first outputcircuit and a respective second output circuit.
 4. The chemicaldetection circuit of claim 3, wherein each pair of tiles share currentsources for driving data signal lines that pass through the columns. 5.The chemical detection circuit of claim 4, wherein the current sourcesare sandwiched between each pair of tiles.
 6. The chemical detectioncircuit of claim 4, wherein the data signal lines passing throughcolumns of each pair of tiles are swizzled between each pair of tiles.7. The chemical detection circuit of claim 1, wherein the plurality offirst columns and the plurality of second columns are interleaved bygroups, each group includes n columns, the number n matches the numberof output pins for each first or second output circuit.
 8. The chemicaldetection circuit of claim 1, wherein each first and second outputcircuits comprises a respective analog-to-digital converter (ADC) togenerate digital outputs.
 9. A chemical detection system, comprising: amother board having at least one central processing unit; an outputdevice coupled to the mother board; and a chemical detection readerboard coupled to the mother board, the chemical detection reader boardhaving a chemical detection circuit comprising: a plurality of firstoutput circuits at a first side of the chemical detection circuit; aplurality of second output circuits at a second side of the chemicaldetection circuit, the second side being opposite to the first side; anda plurality of tiles of pixels each placed between a respective firstoutput circuit and a respective second output circuit, each tilecomprising: four quadrants of pixels, each quadrant comprising: aplurality of first columns; and a plurality of second columnsinterleaved with the plurality of first columns, each first column andsecond column having a plurality of pixels formed in rows, wherein eachfirst column in first and second quadrants is coupled to the respectivefirst output circuit, and each second column in first and secondquadrants is coupled to the respective second output circuit, whereineach first column in third and fourth quadrants is coupled to therespective second output circuit, and each second column in third andfourth quadrants is coupled to the respective first output circuit. 10.The chemical detection system of claim 9, wherein each pixel includes anion-sensitive field effect transistor (ISFET).
 11. The chemicaldetection system of claim 9, wherein the plurality of tiles are lined upin two slices in parallel, each tile from a first slice and acorresponding tile from a second slice form a respective pair of tiles,each pair of tiles are placed between a respective first output circuitand a respective second output circuit.
 12. The chemical detectionsystem of claim 10, wherein each pair of tiles share current sources fordriving data signal lines that pass through the columns.
 13. Thechemical detection system of claim 12, wherein the current sources aresandwiched between each pair of tiles.
 14. The chemical detection systemof claim 10, wherein the data signal lines passing through columns ofeach pair of tiles are swizzled between each pair of tiles.
 15. Thechemical detection system of claim 9, wherein the plurality of firstcolumns and the plurality of second columns are interleaved by groups,each group includes n columns, the number n matches the number of outputpins for each first or second output circuit.
 16. The chemical detectionsystem of claim 9, wherein each first and second output circuitscomprises a respective analog-to-digital converter (ADC) to generatedigital outputs.
 17. The chemical detection system of claim 9, whereinthe chemical detection reader board includes a plurality ofanalog-to-digital converters (ADCs) to convert analog signals from thefirst and second output circuits.
 18. A method to read out data from achemical detection circuit, comprising: selecting a first quadrant of atile to read out data; selecting one group of first columns and onegroup of second columns; reading out data of the group of first columnsfrom a first set of output pins located at a first side of the chemicaldetection circuit; reading out data of the group of second columns froma second set of output pins located at a second side of the chemicaldetection circuit; and repeating selection and data readouts for nextgroups of first columns and second columns till all remaining columns ofthe first quadrant are read out.
 19. The method of claim 18, furthercomprising: incrementing a row count by one; repeating selection anddata readouts for next row of the first quadrant; and after finishingall rows of the first quadrant, continuing selection and data readoutsin groups of first columns and second columns in other quadrants. 20.The method of claim 19, wherein for second quadrant, data of firstcolumns is read out from a respective set of output pins located at thefirst side of the chemical detection circuit, and data of second columnsis read out from a respective set of output pins located at the secondside of the chemical detection circuit.
 21. The method of claim 20,wherein for third and fourth quadrants, data of first columns is readout from respective sets of output pins located at the second side ofthe chemical detection circuit, and data of second columns is read outfrom a respective sets of output pins located at the first side of thechemical detection circuit.
 22. The method of claim 18, furthercomprising: after finishing a row in the first quadrant, incrementingthe row count by one for the first quadrant; continuing selection anddata readouts in groups of first columns and second columns for a row ineach of the other quadrants in turn, incrementing the row count by onefor each quadrant when finished; repeating selection and data readoutsfor next row in each of the quadrants until all of the rows in each ofthe quadrants are read out.
 23. The method of claim 22, wherein forsecond quadrant, data of first columns is read out from a respective setof output pins located at the first side of the chemical detectioncircuit, and data of second columns is read out from a respective set ofoutput pins located at the second side of the chemical detectioncircuit.
 24. The method of claim 23, wherein for third and fourthquadrants, data of first columns is read out from respective sets ofoutput pins located at the second side of the chemical detectioncircuit, and data of second columns is read out from a respective setsof output pins located at the first side of the chemical detectioncircuit.
 25. The method of claim 18, wherein the data being read out areanalog signals.
 26. The method of claim 18, wherein a respective groupof the first columns and a respective group of the second columns form adata channel, the chemical detection circuit bases its internal clocksignals on external channel increment/decrement signals.
 27. The methodof claim 18, wherein the data being read out are digital signals, thedigital signals are converted from analog signals by the chemicaldetection circuit.